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Research To Practice | Oncology Videos
Urothelial Bladder Cancer | Oncology Today with Dr Neil Love: Management of Metastatic Urothelial Bladder Cancer

Research To Practice | Oncology Videos

Play Episode Listen Later Aug 30, 2024 30:32


Featuring an interview with Dr Michiel van der Heijden, including the following topics: Underlying biological mechanisms of the bladder cancer immune micro-environment in the context of response to immune checkpoint inhibition (0:00) Treatment patterns and survival outcomes for patients admitted to the intensive care unit due to immune-related adverse events (3:15) Activity of anti-PD1/PD-L1 and anti-CTLA4 combinations for patients with bladder cancer; role of circulating and urinary tumor DNA in urothelial carcinoma (6:40) Case: A 61-year-old woman with metastatic urothelial bladder cancer (mUBC) treated with first-line enfortumab vedotin and pembrolizumab (19:34) Case: A 63-year-old man with extensive mUBC whose disease progresses on avelumab maintenance receives enfortumab vedotin (25:54) CME information and select publications

ASCO Daily News
Immunotherapy at ASCO24: NADINA and Other Key Studies

ASCO Daily News

Play Episode Listen Later Jun 19, 2024 34:51


Dr. Diwakar Davar and Dr. Jason Luke discuss advances in the neoadjuvant immunotherapy space that were presented at the 2024 ASCO Annual Meeting, including promising outcomes in high-risk melanoma from the NADINA trial, as well as other new treatment options for patients with advanced cancers.    TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I am an associate professor of medicine and the clinical director of the Melanoma Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I am delighted to have my colleague and friend Dr. Jason Luke on the podcast today to discuss key late-breaking abstracts and advances in immunotherapy that were presented at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the associate director of clinical research, and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center.   You will find our full disclosures in the transcript of this episode.  Jason, it's always a pleasure to hear your insights on the key trials in these spaces and to have you back as a guest on this podcast that highlights some of the work, especially advances, that were just presented. Dr. Jason Luke: Well, thanks very much for the invitation. I always love joining the podcast. Dr. Diwakar Davar: We'll start very quickly by talking about some advances and really interesting things that happened both in the context of melanoma but also in immunotherapy in general. And we'll start with what I think was certainly one highlight for me, which was LBA2, the late-breaking abstract on the NADINA trial. It was featured in the Plenary Session, and in this abstract, Dr. Christian Blank and colleagues reported on the results of this phase 3 trial of neoadjuvant ipi-nivo. This is the flipped dose of ipi1/nivo3 versus adjuvant nivolumab in PD-1 naive, macroscopic, resectable, high-risk stage 3 melanoma.  By way of background, neoadjuvant immunotherapy for those listening is an area of increasing interest for drug developers and development for both approved and novel agents. Neoadjuvant immunotherapy has been studied with multiple approved agents, including PD-1 monotherapy, PD-1 LAG-3, PD-1 CTLA-4, T-VEC, as well as investigational agents and multiple randomized and non-randomized studies. The benchmark pathologic response rates with these agents range from 17% PCR with PD-1 monotherapy, 45% to 55% PCR with PD-1 CTLA-4 combination therapy, and slightly higher 57% PCR with PD-1 LAG-3 has recently reported by Dr. Rodabe Amaria from MD Anderson. However, as we embark on phase 3 comparisons for various neoadjuvant compared to adjuvant immunotherapy trials and combinations, we're increasingly moving towards event-free survival as the primary endpoint for neoadjuvant versus adjuvant studies. And this was most recently studied in the context of SWOG S1801, a study that was led by Dr. Sapna Patel.  So, Jason, before we start on NADINA, can you briefly summarize the SWOG S1801 trial and the event-free survival statistic reported by Dr. Patel and her colleagues? Dr. Jason Luke: Well, absolutely. And these data were reported at ESMO about two years ago and then in the New England Journal last year. The S1801 study answered a very simple question: What would happen if you took three of the doses of standard adjuvant therapy with pembrolizumab and moved them prior to surgery? And on a high level, the study is as simple as that. And many of us were somewhat skeptical of this trial design because we thought that just moving the doses earlier may not actually have a major impact.  In the study, you alluded to the event-free survival statistic, and that alludes to what was considered an event. And so, without reading all of it, there were several different aspects that were included in terms of time, based on the date of randomization until the first of a series of events, such as disease progression, toxicity from treatment, if the patient was unable to go to surgery or had surgical complications, or if they had delay in starting the adjuvant therapy due to toxicity, and obviously, recurrence of melanoma or death from any cause. In that context, merely moving the 3 doses of pembrolizumab to the neoadjuvant setting saw an improvement in this two-year event free survival to 72% for the neoadjuvant therapy compared to 49% for the adjuvant therapy. That was quite an outstanding change. And again, noting the power of neoadjuvant treatment, really dictating the impact of anti PD-1, again, just with 3 doses moving from adjuvant into the neoadjuvant setting, and I think all of us were somewhat surprised to see that magnitude of a benefit. But it set up the current study very well, where we now look at combination therapy. Dr. Diwakar Davar: So let's move on to the phase 3 NADINA trial. Do you want to perhaps discuss the study design, particularly focusing on the EFS primary endpoint and maybe also touching on the different schedules? So, SWOG S1801 was a neoadjuvant study of 3 cycles of pembrolizumab and how did that compare and contrast to the neoadjuvant combination that was studied in NADINA? Dr. Jason Luke: Well, as you alluded to, NADINA investigated the regimen of nivolumab plus ipilimumab and compared that against adjuvant therapy with nivolumab alone. So, in the study, as you alluded, the dose and schedule of the two drugs used was nivolumab at 3 milligrams per kilogram, and ipilimumab with 1 milligram per kilogram. That was based on a series of signal finding and safety studies that had been previously done by the same group of authors identifying that as the optimal treatment regimen. And it's worth noting that's slightly different than the labeled indication that's generally used for those same drugs for metastatic melanoma, albeit that the NCCN also endorses this schedule. So, in the trial, 423 patients were randomized, 1:1 to receive either neoadjuvant therapy with those 2 doses of nivolumab plus ipilimumab as compared with standard adjuvant therapy with nivolumab following surgery.   Now, one interesting tweak was that there was an adaptive nature to the study, meaning that patients had a fiducial placed at the index lymph node, and after the neoadjuvant therapy in that arm, that lymph node was removed. And if the patient had a major pathological response, they did not go on to receive the adjuvant portion of the treatment. So it was adaptive because those patients who did very well to the neoadjuvant did not require the adjuvant portion. And in those patients who did not achieve a major pathological response, they could go on to have the adjuvant therapy. And that also included the BRAF therapy for those whose tumors were BRAF mutants.  It's also worth pointing out that the definition of event free survival was slightly different than in the S1801 study that was alluded to just a second ago. And here, EFS was defined from the date of randomization until progression due to melanoma or due to treatment. So that's slightly different than the definition in the S1801 trial. So, a somewhat complicated study, but I really applaud the authors because I think this study does mirror what we would likely be doing in actual clinical practice.  Dr. Diwakar Davar: So, just to briefly summarize the efficacy, and then to get your comments on this, the path response, the PCR rate was 47%. The major pathologic response rate, which is the proportion of patients with between 0% to 1/10% of residual viable tumors, was about 12%. And for a major pathologic response rate of 0% to 10% of 59%. And then the rest of the patients had either pathologic partial response, which was 10% to 50%, or pathologic non response or 50% or greater residual viable tumor, all assessed using central pathology grades. The one year RFS was 95% in the FDR patient population versus 76% in the pathologic partial response patient population, 57% in the pathologic non response patient population. So how do you view these results? Can you context the FDR rates and the EFS rates from NADINA relative to nivo-rela and also potentially SWOG 1801? Dr. Jason Luke: Well, I think these are very exciting results. I think that for those of us that have been following the field closely, they're actually not especially surprising because they mirror several studies that have come before them. When we put them in context with other studies, we see that these rates of major pathological response are consistent with what we've seen in phase 2 studies. They're relatively similar. Or I should say that the results from nivolumab and relatlimab, which was also pursued in a phase 2 study of somewhat similar design, are somewhat similar to this. So, combination immunotherapy does look to deliver a higher major pathological response than pembrolizumab alone, as was known in S1801. Which of course, the caveat being is these are cross control comparisons that we need to be careful about. So I think all of these are active regimens, and I think adding a second agent does appear to enhance the major pathologic response rates. When we look at the event free survival, we see something similar, which is that numerically it looks to be that combination immunotherapy delivers a higher event free survival rate. And that looks to be rather meaningful given the difference in the hazard ratios that were observed between these various studies. And here in the NADINA study, we see that 0.3 hazard ratio for EFS is just extremely impressive.  So the abstract then, from ourselves, out of these specific studies, what does this mean more broadly in the real world, where patients exist and the rest of the landscape for clinical trials? I think we can't take enough time to stop for a second and just think about what a revolution we've come forward in with immune checkpoint blockade and melanoma. When I started my career, now, more than 15 years ago, melanoma was the cancer that made cancer bad. And now here we say, in the highest risk of perioperative patients, we can deliver 2 doses of nivolumab and ipilimumab, and essentially half of the patients then don't need to go on, and more than half the patients don't need to go on to have a full surgery and don't need adjuvant therapy. And from what we could tell of a very, very low risk of every heavy recurrence of melanoma. Of course, there's the other half of patients where we still need to do better, but these are just fantastic results and I think highly meaningful for patients.   In the context of ongoing clinical trials, another abstract that was presented during the meeting was the update to the individualized neoantigen therapy, or V940 with pembrolizumab or against pembrolizumab alone. That's the KEYNOTE-942 study. In that study, they presented updated data at two and a half years for relapse free survival, noting a 75% rate without relapse. So those results are also highly intriguing. And these are in a similar population of very high risk patients. And so I think most of us believe that neoadjuvant therapy with this study in NADINA is now confirmed as the priority approach for patients who present with high-risk stage 3 disease. So that would be bulky disease picked up on a scan or palpable in a clinic. I think essentially all of us now believe patients should get preoperative immunotherapy. We can debate which approach to take, and it may vary by an individual patient's ability to tolerate toxicity, because, of course, multi agent immunotherapy does have increased toxicity relative to anti PD-1 alone. But we'll have to wait now for the full phase 3 results from the V940 individualized neoantigen therapy. And if those come forward, that will be an extremely attractive approach to think about for patients who did not achieve a major pathological response to neoadjuvant therapy, as well as of course to the other populations of patients with melanoma where we otherwise currently give adjuvant therapy stage 2B all the way through stage 4 resected. It's an amazing time to think about perioperative therapy in melanoma. Dr. Diwakar Davar: So this is clearly outstanding data, outstanding news. Congratulations to the investigators for really doing what is an investigative initiated trial conducted across multiple continents with a huge sample size. So this clearly appears to be, at this point in time at least, a de facto standard. But is this going to be FDA-approved, guideline-approved, or is it possible in your mind? Dr. Jason Luke: Well, that's an interesting question. This study was not designed with the intent to necessarily try to register this treatment regimen with the FDA. One would have to take a step back and say, with how powerful these data appear, it sort of seemed like it would be too bad if that doesn't happen. But all the same, I think the community and those of us who participate in guideline recommendations are fully supportive of this. So, I think we will see this move into compendium listings that support insurance approval, I think, very, very quickly. So, whether or not this actually becomes formally FDA approved or is in the guidelines, I think this should become the standard approach that is considered for patients, again presenting with high-risk stage 3 disease.  Dr. Diwakar Davar: Fantastic. So now we're going to go in and talk about a slightly different drug, but also from the melanoma context, and that is the safety and efficacy of RP1 with nivolumab in the context of patients with melanoma who are PD-1 failures. So, this is Abstract 9517. And in this abstract, our academic colleagues essentially talked about these data, and we'll start by describing what RP1 is. RP1 essentially is a HSV-1 based oncolytic immunotherapy. And RP1 expresses GM-CSF as well as a fusogenic protein, GALV-GP-R-. And in this abstract, Dr. Michael Wong from MD Anderson and colleagues are reporting the results of IGNYTE, which is a phase I trial of intratumoral RP1 co-administered with systemic nivolumab in patients with advanced metastatic treatment refractory cutaneous melanoma. And the data presented in this abstract represents data from a registration directed, abbreviated as RD, registration directed cohort of RP1 plus nivolumab in PD-1 refractory melanoma. So, let's start with the description of the cohort.  Dr. Jason Luke: Right. So, in this study, there were a total of 156 patients who were presented, and that included an initial safety and dose finding group of 16, as well as the RD cohort, as you noted, of 140 patients. And it's important to point out that this was a cohort that was selected for a very strict definition of progression on anti PD-1, or a combination immunotherapy as their immediately prior treatment. So, all of the patients in the cohort had exposure to anti PD-1, and 46% of them had anti PD-1 plus anti CTLA4, nivolumab and ipilimumab as their immediately prior therapy. This was also a group of relatively high-risk patients when one considers stage. So, within the stage 4 population, the entry here included 51% who had stage M1B, C, and D melanoma. And that is worth pointing out because this is an injectable therapy. So, trials like this in the past have tended to be biased towards earlier stage, unresectable or metastatic melanoma, meaning stage 3B, 3C, 3D and then stage 4m1a. Again, to emphasize the point here, these were pretreated patients who had a strict definition of anti PD-1 resistance, and over half of them, in fact, had high-risk visceral metastatic disease.  In that context, it's very interesting to observe that the overall response rate was described in the total population, as 31%, and that included 12% who achieved complete response. And so, again, to make sure it's clear, we're talking about a treatment where the oncolytic virus is injected into one or multiple sites of recurrent disease, and then the patients administer nivolumab as per standard. And so, I think these data are quite intriguing. Again, such a high- risk population and their maturity now, with a follow-up of over a year, I think, makes this look to be a very interesting treatment option.  Dr. Diwakar Davar: I guess on that topic of mature follow-up, it probably would be important for us to inform our audience that the top line data for the primary analysis was actually just released, I think, earlier today, and wherein the central confirmed objective response rate was 34% by modified RECIST and 33% by RECIST, clearly indicating that these responses, as you noted, very treatment refractory patient population, these responses were clearly very durable. So, you mentioned that there were responses seen in uninjected visceral lesions, responses seen in both PD-1 and PD-1 CTLA-4 refractory patients. Can you talk a little bit about the response rate in these high-risk subgroups, the uninjected visceral lesions, the patients who had both combination checkpoint and epidural refractory response rate by primary PD-1 resistance.  Dr. Jason Luke: Sure. You know, I think, again, to emphasize this point in the study, we saw that there were responses in the non-injected lesions, and I think it's really important to emphasize that. Some have referred to this as a putative abscopal like effect, similar to what is described in radiation. But it implies that local treatment with the oncolytic virus is triggering a systemic immune response. In the higher risk patient population, we'll note that whereas the overall response rate in PD-1 refractory patients was 34%, in the combination of PD-1 and CTLA-4 refractory patients, the response rate was 26%. So, [this is] still very good. And when we looked at that split by stage, as I alluded to before, in the population of patients that had, what you might call earlier unresectable diseases, so 3B through 4A, the response rate was 38%, and in the stage 4 M1b through M1d, it was 25%. So slightly lower, but still very good. And that would be as expected, because, of course, the patients with visceral metastatic disease have more advanced disease, but those response rates look quite good. Again, looking at the combination refractory population as well as the more high-risk disease. Dr. Diwakar Davar: So, clearly, these are very promising data and exciting times for multiple investigators in the field and the company, Replimune, as well. So, what are the next steps? I believe that a registration trial is planned, essentially, looking at this with the goal of trying to get this combination registered. Can you tell us a little bit about IGNYTE-3, the trial design, the control arm, and what you foresee this trial doing over the next couple of years?  Dr. Jason Luke: So, as this agent has been maturing, it's worth pointing out that the company that makes this molecule, called RP1, but I guess now we'll have to get used to this name vusolimogene oderparepvec as the actual scientific term, they have been having ongoing discussions with the FDA, and there is the potential that this agent could come forward on an accelerated path prior to the results being released from a phase 3 trial. That being said, the phase 3 confirmatory study, which is called the IGNYTE-3 study, is in the process of being launched now. And that's a study investigating this molecule in combination with nivolumab, as was alluded to earlier, and a randomized phase 3 design, where that combination is compared with a physician's choice, essentially a chemotherapy-based option.   In that study, it will be 400 patients with stage 3B through stage 4; patients will have progressed on anti PD-1, either as a combination or in sequence, and then come on the study to be randomized to either vusolimogene oderparepvec plus nivolumab versus that physician's choice. And the physician's choice includes chemotherapy agents, but also nivolumab plus relatlimab as another option, or an anti PD-1 monotherapy, if that's deemed to be a reasonable option by the treating investigator. And the primary endpoint of that study is overall survival. And unfortunately, in this highly refractory patient population, that's something that may not take long to identify with key secondary endpoints of progression free survival, as well as overall response rate. I'm quite enthusiastic about this study, given these data, which have now been centrally confirmed as you alluded to before. I think this is a very exciting area of investigation and really crossing my fingers that this may be perhaps the first locally administered therapy which does appear to have a systemic impact that can hold up in phase 3. Dr. Diwakar Davar: Very, very, very exciting results. And I guess it's worthwhile pointing out that this company also has got, I think, multiple studies planned with both RP1 and cutaneous squamous cell carcinoma in a solid organ transplant patient population where single agent activity has already been reported by Dr. Migden at prior meetings, as well as a novel trial of potentially RP2 metastatic uveal melanoma. So we'll now pivot to Abstract 6014. So, 6014 is a drug by a company known as Merus. Essentially, it's a very novel agent. Merus essentially is a company that is specialized in making bicyclics and tricyclics. And these are not bicycles or tricycles, but rather drugs that essentially are bispecific antibodies. And Merus essentially has come up with petosemtamab. I think we're going to have to figure out better names for all of these drugs at some point. But petosemtamab, or MCLA-158, essentially is a bicyclic, targeting both EGFR as well as LGR-5. So EGR-5, of course, is a known oncogenic driver in multiple tumor types, squamous, including non small cell lung cancer, cutaneous squamous cell carcinoma, but also head and neck squamous cell carcinoma. And LGR-5 essentially is leucine-rich repeat-containing G-protein coupled receptor 5, but it's a receptor in cancer stem cells and certainly highly expressed in head neck squam. And MCLA-158, or petosemtamab is a IgG one bispecific with ADCC-activity because of IgG1 backbone co-targeting EGFR and LGR5. Merus had earlier results that evaluated petosemtamab monotherapy. They defined the RP2D and second- and third-line head and neck blastoma patients with a respectable response rate of 37% investigator-assessed ORR with six months median DoR, and this was published by Ezra Cohen about a year or so ago.  In this abstract, Dr. Fayette and colleagues report on the results of the MCLA-158-CL01 trial, which is a trial of pembrolizumab plus petosemtamab in one front line head and neck squamous cell population. So maybe let's start with the description of the cohort. And it is a small trial, but we'll be able, I think, to dig into a little bit about why this might be exciting. Dr. Jason Luke: Yes. So, as alluded to, it's not the biggest trial as yet, but there were 26 patients with anti PD-1 treatment naive head and neck squamous cell carcinoma. And all the patients in the study did receive, as you alluded to, pembrolizumab plus petosemtamab. Based on the label for pembrolizumab, all the patients in this study were PDL-1 positive. So that's one point that it's worth pointing out to make sure that that's understood. This is the population of patients who would be expected to benefit from pembrolizumab in the first place. Now, in the abstract, they reported out only 10 response evaluable patients, but they updated that in the actual slides of presentation at the meeting. So among 24 patients that were alluded to, 67% were described as having had a response, although some of those were yet to be confirmed responses. And when it was evaluated by PDL-1 status, there didn't seem to be a clear enrichment of response in the PD-1 positive more than 20% group, as compared to the 1-19% group. That isn't especially surprising because that was a trend that one would see, presumably with pembrolizumab alone. But overall, I think these data are pretty exciting in terms of a preliminary study. Dr. Diwakar Davar: You know, you mentioned that the objective response rate was high, almost 60-something%. The prognosis of these patients is generally poor. The OS is typically thought of as between 6-15 months. And based on KEYNOTE-048, which was led by Dr. Burtness and colleagues, the standard of care in the setting is pembrolizumab +/- platinum based chemotherapy regimens. Allowing for the fact that we only have 10 patients here, how do you think these results stack up against KEYNOTE-048? And you made a very important point earlier, which was, by definition, pembro is on label only for the CPS. So PDL-1 score, at least in head and neck squamous cell carcinoma CPS and not TPS. But in the CPS 1% or greater patient population, where pembro is on label, how do these results stack up against the KEYNOTE-048 results. Dr. Jason Luke: Right. KEYNOTE-048 is considered the seminal study that dictates frontline treatment in head and neck cancer. And before we dive into this too far, we do want to acknowledge that here we're comparing 26 patients versus a phase 3 trial. So, we're not trying to get too far ahead of ourselves, but this is just a preliminary comparison. But in KEYNOTE-048, as you alluded to, two regimens were superior to chemotherapy. One was the pembrolizumab monotherapy, as well as pembrolizumab plus chemotherapy. So again, the study overall survival, of course, was much higher, the PDL-1 positive subgroup, which is what dictated the unlabeled use of this. But response to pembro monotherapy in that population of patients is still modest. We're talking about upwards of 20-30%. So, if you compare that to, again, preliminary evidence here from this trial of only 24 patients, that response rate of 60% seems extremely high. And so even if that were to come down somewhat in a larger data series of patients, that still looks to be quite promising as a treatment regimen, that might eventually even be chemotherapy sparing for this population of patients. I think this raises a lot of eyebrows that perhaps this dual targeting approach, EGFR and LDR-5, may bring something really important to the field that evolves it. Dr. Diwakar Davar: So, what are the next steps for petosemtamab? You mentioned that the activity was interesting. Are we going to see a larger trial? Any thoughts on where things are going to go?  Dr. Jason Luke: Well, based on the phase 2 data of petosemtamab alone, even without pembrolizumab, the molecule had already been given fast track designation by FDA, which means allowing for greater communication between the drug sponsor in the FDA and designing a seminal study design. One would assume that this trial will be rapidly expanded quite greatly, perhaps to 100 or 200 patients, to try to flush out what the real response rate is in a more meaningful number of patients. But I think these data will probably also trigger the design and probably near-term evaluation or expedited acceleration of a phase III clinical trial design that would potentially validate this against the current standard of care. So, I'm pretty excited. I think we'll see a lot more about this agent in the relatively near future. Dr. Diwakar Davar: So, finally, we'll pivot to the last abstract that we're going to talk about, which is Abstract 2504. It's a relatively interesting target, CCR8 monoclonal antibody. But this is the efficacy and safety of LM-108, and LM-108 is an anti CCR8 monoclonal antibody that is being developed by LaNova Medicine. And the results that are described, actually a pool set of results of combinations of LM-108 with anti PD-1, two separate anti PD-1, in patients with gastric cancer, mostly done ex-U.S., which is interesting because of this patient population, and it's a pool result of several, 3 phase 1 and 2 studies.  LM-108 is an Fc-optimized anti CCR8 monoclonal antibody that selectively depletes tumor infiltrating Tregs. The abstract reported a pooled analysis of three phase 1, 2 trials with 3 different NCT numbers that all evaluated the efficacy of LM-108 and anti PD-1 in patients with gastric cancer. So, let's start with the description of the cohort. Maybe, Jason, you can tell us a little bit about before you start, as you describe the cohort, sort of what we know, editorially speaking, about the difficulty with which Tregs depletion has been tried and obviously failed up until now in the tumor microenvironment. Dr. Jason Luke: Right. I think that's a really interesting comment. And so, for decades, in fact, targeting regulatory T-cell to alleviate immune exclusion in the tumor microenvironment has been of interest in immuno-oncology. And in preclinical mouse models, it seems quite clear that such an approach can deliver therapeutic efficacy. However, by contrast, in human clinical trials, various different Treg depleting strategies have been attempted, and there's really little to no evidence that depleting Tregs from human tumors actually can deliver therapeutic responses. And by that we're referring to CD-25 antibodies. The drug ipilimumab, the CTLA-4 antibody, was punitively described as a Tregs depleter preclinically, but that doesn't seem to be the case in patients. And so, in that background, this is quite an eye raiser that an anti CCR8 antibody could be driving this effect. Now, before we talk about the results of this trial, I will point out, however, that given the Fc-optimization, it's entirely possible that the Tregs are being depleted by this mechanism, but that more could also be going on. Because Fc gamma RII binding by this antibody that could be nonspecific also has the potential to trigger immune responses in the tumor microenvironment, probably mediated by myeloid cells. So I think more to come on this. If this turns out to be the first meaningful Tregs depletor that leads to therapeutic efficacy, that would be very interesting. But it's also possible this drug could have multiple mechanisms.  So, having said all of that, in the clinical trial, which was a pooled analysis, like you mentioned, of LM-108 in combination with anti PD-1 of a couple different flavors, there were 48 patients treated either with LM-108, with pembrolizumab, or with toripalimab, which is another anti PD-1 antibody. On the drug combination was, generally speaking, pretty well tolerated, noting grade 3 treatment related adverse events in the range of 38%, which is somewhat expected given combination immunotherapy. We talked about nivolumab and ipilimumab before, which, of course, gives even higher rates of immune-related adverse events, with the most common toxicities being anemia, lipase elevations, rash, ALC decrease; albeit, quite manageable. Dr. Diwakar Davar: So, what about the objective response rate? Can you contextualize the efficacy? And as you do that, maybe we'll think about what you'd expect in the context of, say, gastric cancer, especially in patients who've never really had a prior checkpoint inhibitor before. What do you think about the ORR? What do you think about the relative efficacy of this combination? Dr. Jason Luke: Well, so, in the study, they described overall response rate in the 36 patients as 36% and described immediate progression for survival of about 6.5 months. And so that was among patients who were treatment naive. And in second-line patients, they actually described an even higher response rate, although it was only 11 patients, but they're at 64%. And so, I think those data look to be somewhat interesting. When I was actually scrutinizing the actual data presented, it was of some interest to note that the quality of responses seemed to be about as good on the lower dose of LM-108, so 3 milligrams per kilogram as compared to 10 milligrams per kilogram. I think there's definitely more to learn here to try to optimize the dose and to fully understand what the overall efficacy of this treatment combination would be.  I would emphasize that in this disease, I think novel treatment strategies are certainly warranted. While anti PD-1 with chemotherapy has moved the needle in terms of standard of care treatment, it's really only a minor subset of patients who derive durable long-term benefit like we normally associate with immune checkpoint blockade. I think these are preliminary data. They're very intriguing.   You alluded to earlier that this population of patients was an Asian data set, and it is well known that the efficacy of chemotherapy and immunotherapy does appear to be somewhat enhanced in Asian populations, and that goes to distributions of metastasis and tumor microenvironment effects, etc. Very difficult to try to tease any of that out in this abstract, other than to look at these data and suggest that this is pretty interesting, both from a novel therapeutic approach, we talked about the Tregs consideration, but also straight up on the efficacy because I think if these data could hold up in a larger number of patients, and particularly in a western population of patients, I think it would be very intriguing. Dr. Diwakar Davar: Certainly, ASCO 2024 had a lot of interesting data, including data from targeted agents, the LAURA trial, ADCs. But just focusing on the immune therapy subset, we certainly saw a lot of great advances in patients who were treated with neoadjuvant as well as relapse refractory disease in the context of RP1 and then a couple of newer agents such as this petosemtamab as well as LM-108. And of course, we cannot forget to highlight the extended DMFS data from the pembro vaccine study from KEYNOTE-942.  Jason, as always, thank you for taking a little bit of time out of your extremely busy schedule to come and give us insights as to how these agents are impacting the landscape. We really value your input and so thank you very much.  Dr. Jason Luke: Thank you for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for your time today. You will find the links to all the abstracts that we discussed in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. So, thank you.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:       Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Jason Luke:    Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Ground Truths
Charlie Swanton: A Master Class on Cancer

Ground Truths

Play Episode Listen Later Jun 14, 2024 55:38


The most enthralling conversation I've ever had with anyone on cancer. It's with Charlie Swanton who is a senior group leader at the Francis Crick Institute, the Royal Society Napier Professor in Cancer and medical oncologist at University College London, co-director of Cancer Research UK.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with audio links and many external linksEric Topol (00:07):Well, hello, this is Eric Topol with Ground Truths, and I am really fortunate today to connect us with Charlie Swanton, who is if not the most prolific researcher in the space of oncology and medicine, and he's right up there. Charlie is a physician scientist who is an oncologist at Francis Crick and he heads up the lung cancer area there. So Charlie, welcome.Charles Swanton (00:40):Thank you, Eric. Nice to meet you.Learning from a FailureEric Topol (00:43):Well, it really is a treat because I've been reading your papers and they're diverse. They're not just on cancer. Could be connecting things like air pollution, it could be Covid, it could be AI, all sorts of things. And it's really quite extraordinary. So I thought I'd start out with a really interesting short paper you wrote towards the end of last year to give a sense about you. It was called Turning a failing PhD around. And that's good because it's kind of historical anchoring. Before we get into some of your latest contributions, maybe can you tell us about that story about what you went through with your PhD?Charles Swanton (01:26):Yeah, well thank you, Eric. I got into research quite early. I did what you in the US would call the MD PhD program. So in my twenties I started a PhD in a molecular biology lab at what was then called the Imperial Cancer Research Fund, which was the sort of the mecca for DNA tumor viruses, if you like. It was really the place to go if you wanted to study how DNA tumor viruses worked, and many of the components of the cell cycle were discovered there in the 80s and 90s. Of course, Paul Nurse was the director of the institute at the time who discovered cdc2, the archetypal regulator of the cell cycle that led to his Nobel Prize. So it was a very exciting place to work, but my PhD wasn't going terribly well. And sort of 18, 19 months into my PhD, I was summoned for my midterm reports and it was not materializing rapidly enough.(02:25):And I sat down with my graduate student supervisors who were very kind, very generous, but basically said, Charlie, this isn't going well, is it? You've got two choices. You can either go back to medical school or change PhD projects. What do you want to do? And I said, well, I can't go back to medical school because I'm now two years behind. So instead I think what I'll do is I'll change PhD projects. And they asked me what I'd like to do. And back then we didn't know how p21, the CDK inhibitor bound to cyclin D, and I said, that's what I want to understand how these proteins interact biochemically. And they said, how are you going to do that? And I said, I'm not too sure, but maybe we'll try yeast two-hybrid screen and a mutagenesis screen. And that didn't work either. And in the end, something remarkable happened.(03:14):My PhD boss, Nic Jones, who's a great guy, still is, retired though now, but a phenomenal scientist. He put me in touch with a colleague who actually works next door to me now at the Francis Crick Institute called Neil McDonald, a structural biologist. And they had just solved, well, the community had just solved the structure. Pavletich just solved the structure of cyclin A CDK2. And so, Neil could show me this beautiful image of the crystal structure in 3D of cyclin A, and we could mirror cyclin D onto it and find the surface residue. So I spent the whole of my summer holiday mutating every surface exposed acid on cyclin D to an alanine until I found one that failed to interact with p21, but could still bind the CDK. And that little breakthrough, very little breakthrough led to this discovery that I had where the viral cyclins encoded by Kaposi sarcoma herpes virus, very similar to cyclin D, except in this one region that I had found interactive with a CDK inhibitor protein p21.(04:17):And so, I asked my boss, what do you think about the possibility this cyclin could have evolved from cyclin D but now mutated its surface residues in a specific area so that it can't be inhibited by any of the control proteins in the mammalian cell cycle? He said, it's a great idea, Charlie, give it a shot. And it worked. And then six months later, we got a Nature paper. And that for me was like, I cannot tell you how exciting, not the Nature paper so much as the discovery that you were the first person in the world to ever see this beautiful aspect of evolutionary biology at play and how this cyclin had adapted to just drive the cell cycle without being inhibited. For me, just, I mean, it was like a dream come true, and I never experienced anything like it before, and I guess it's sizes the equivalent to me of a class A drug. You get such a buzz out of it and over the years you sort of long for that to happen again. And occasionally it does, and it's just a wonderful profession.Eric Topol (05:20):Well, I thought that it was such a great story because here you were about to fail. I mean literally fail, and you really were able to turn it around and it should give hope to everybody working in science out there that they could just be right around the corner from a significant discovery.Charles Swanton (05:36):I think what doesn't break you makes you stronger. You just got to plow on if you love it enough, you'll find a way forward eventually, I hope.Tracing the Evolution of Cancer (TRACERx)Eric Topol (05:44):Yeah, no question about that. Now, some of your recent contributions, I mean, it's just amazing to me. I just try to keep up with the literature just keeping up with you.Charles Swanton (05:58):Eric, it's sweet of you. The first thing to say is it's not just me. This is a big community of lung cancer researchers we have thanks to Cancer Research UK funded around TRACERx and the lung cancer center. Every one of my papers has three corresponding authors, multiple co-first authors that all contribute in this multidisciplinary team to the sort of series of small incremental discoveries. And it's absolutely not just me. I've got an amazing team of scientists who I work with and learn from, so it's sweet to give me the credit.Eric Topol (06:30):I think what you're saying is really important. It is a team, but I think what I see through it all is that you're an inspiration to the team. You pull people together from all over the world on these projects and it's pretty extraordinary, so that's what I would say.Charles Swanton (06:49):The lung community, Eric, the lung cancer community is just unbelievably conducive to collaboration and advancing understanding of the disease together. It's just such a privilege to be working in this field. I know that sounds terribly corny, but it is true. I don't think I recall a single email to anybody where I've asked if we can collaborate where they've said, no, everybody wants to help. Everybody wants to work together on this challenge. It's just such an amazing field to be working in.Eric Topol (07:19):Yeah. Well I was going to ask you about that. And of course you could have restricted your efforts or focused on different cancers. What made you land in lung cancer? Not that that's only part of what you're working on, but that being the main thing, what drew you to that area?Charles Swanton (07:39):So I think the answer to your question is back in 2008 when I was looking for a niche, back then it was lung cancer was just on the brink of becoming an exciting place to work, but back then nobody wanted to work in that field. So there was a chair position in thoracic oncology and precision medicine open at University College London Hospital that had been open, as I understand it for two years. And I don't think anybody had applied. So I applied and because I was the only one, I got it and the rest is history.(08:16):And of course that was right at the time when the IPASS draft from Tony Mok was published and was just a bit after when the poster child of EGFR TKIs and EGFR mutant lung cancer had finally proven that if you segregate that population of patients with EGFR activating mutation, they do incredibly well on an EGFR inhibitor. And that was sort of the solid tumor poster child along with Herceptin of precision medicine, I think. And you saw the data at ASCO this week of Lorlatinib in re-arranged lung cancer. Patients are living way beyond five years now, and people are actually talking about this disease being more like CML. I mean, it's extraordinary the progress that's been made in the last two decades in my short career.Eric Topol (09:02):Actually, I do want to have you put that in perspective because it's really important what you just mentioned. I was going to ask you about this ASCO study with the AKT subgroup. So the cancer landscape of the lung has changed so much from what used to be a disease of cigarette smoking to now one of, I guess adenocarcinoma, non-small cell carcinoma, not related to cigarettes. We're going to talk about air pollution in a minute. This group that had, as you say, 60 month, five year plus survival versus what the standard therapy was a year plus is so extraordinary. But is that just a small subgroup within small cell lung cancer?Charles Swanton (09:48):Yes, it is, unfortunately. It's just a small subgroup. In our practice, probably less than 1% of all presentations often in never smokers, often in female, never smokers. So it is still in the UK at least a minority subset of adenocarcinomas, but it's still, as you rightly say, a minority of patients that we can make a big difference to with a drug that's pretty well tolerated, crosses the blood-brain barrier and prevents central nervous system relapse and progression. It really is an extraordinary breakthrough, I think. But that said, we're also seeing advances in smoking associated lung cancer with a high mutational burden with checkpoint inhibitor therapy, particularly in the neoadjuvant setting now prior to surgery. That's really, really impressive indeed. And adjuvant checkpoint inhibitor therapies as well as in the metastatic setting are absolutely improving survival times and outcomes now in a way that we couldn't have dreamt of 15 years ago. We've got much more than just platinum-based chemo is basically the bottom line now.Revving Up ImmunotherapyEric Topol (10:56):Right, right. Well that actually gets a natural question about immunotherapy also is one of the moving parts actually just amazing to me how that's really, it's almost like we're just scratching the surface of immunotherapy now with checkpoint inhibitors because the more we get the immune system revved up, the more we're seeing results, whether it's with vaccines or CAR-T, I mean it seems like we're just at the early stages of getting the immune system where it needs to be to tackle the cancer. What's your thought about that?Charles Swanton (11:32):I think you're absolutely right. We are, we're at the beginning of a very long journey thanks to Jim Allison and Honjo. We've got CTLA4 and PD-1/PDL-1 axis to target that's made a dramatic difference across multiple solid tumor types including melanoma and lung cancer. But undoubtedly, there are other targets we've seen LAG-3 and melanoma and then we're seeing new ways, as you rightly put it to mobilize the immune system to target cancers. And that can be done through vaccine based approaches where you stimulate the immune system against the patient's specific mutations in their cancer or adoptive T-cell therapies where you take the T-cells out of the tumor, you prime them against the mutations found in the tumor, you expand them and then give them back to the patient. And colleagues in the US, Steve Rosenberg and John Haanen in the Netherlands have done a remarkable job there in the context of melanoma, we're not a million miles away from European approvals and academic initiated manufacturing of T-cells for patients in national health systems like in the Netherlands.(12:50):John Haanen's work is remarkable in that regard. And then there are really spectacular ways of altering T-cells to be able to either migrate to the tumor or to target specific tumor antigens. You mentioned CAR-T cell therapies in the context of acute leukemia, really extraordinary developments there. And myeloma and diffuse large B-cell lymphoma as well as even in solid tumors are showing efficacy. And I really am very excited about the future of what we call biological therapies, be it vaccines, an antibody drug conjugates and T-cell therapies. I think cancer is a constantly adapting evolutionary force to be reckoned with what better system to combat it than our evolving immune system. It strikes me as being a future solution to many of these refractory cancers we still find difficult to treat.Eric Topol (13:48):Yeah, your point is an interesting parallel how the SARS-CoV-2 virus is constantly mutating and becoming more evasive as is the tumor in a person and the fact that we can try to amp up the immune system with these various means that you just were reviewing. You mentioned the other category that's very hot right now, which is the antibody drug conjugates. Could you explain a bit about how they work and why you think this is an important part of the future for cancer?Antibody-Drug ConjugatesCharles Swanton (14:26):That's a great question. So one of the challenges with chemotherapy, as you know, is the normal tissue toxicity. So for instance, neutropenia, hair loss, bowel dysfunction, diarrhea, epithelial damage, essentially as you know, cytotoxics affect rapidly dividing tissues, so bone marrow, epithelial tissues. And because until relatively recently we had no way of targeting chemotherapy patients experienced side effects associated with them. So over the last decade or so, pioneers in this field have brought together this idea of biological therapies linked with chemotherapy through a biological linker. And so one poster chart of that would be the drug T-DXd, which is essentially Herceptin linked to a chemotherapy drug. And this is just the most extraordinary drug that obviously binds the HER2 receptor, but brings the chemotherapy and proximity of the tumor. The idea being the more drug you can get into the tumor and the less you're releasing into normal tissue, the more on tumor cytotoxicity you'll have and the less off tumor on target normal tissue side effects you'll have. And to a large extent, that's being shown to be the case. That doesn't mean they're completely toxicity free, they're not. And one of the side effects associated with these drugs is pneumonitis.(16:03):But that said, the efficacy is simply extraordinary. And for example, we're having to rewrite the rule books if you like, I think. I mean I'm not a breast cancer physician, I used to be a long time ago, but back in the past in the early 2000s, there was HER2 positive breast cancer and that's it. Now they're talking about HER2 low, HER2 ultra-low, all of which seem to in their own way be sensitive to T-DXd, albeit to a lower extent than HER2 positive disease. But the point is that there doesn't seem to be HER2 completely zero tumor group in breast cancer. And even the HER2-0 seem to benefit from T-DXd to an extent. And the question is why? And I think what people are thinking now is it's a combination of very low cell service expression of HER2 that's undetectable by conventional methods like immunohistochemistry, but also something exquisitely specific about the way in which HER2 is mobilized on the membrane and taken back into the cell. That seems to be specific to the breast cancer cell but not normal tissue. So in other words, the antibody drug conjugate binds the tumor cell, it's thought the whole receptor's internalized into the endosome, and that's where the toxicity then happens. And it's something to do with the endosomal trafficking with the low level expression and internalization of the receptor. That may well be the reason why these HER2 low tumors are so sensitive to this beautiful technology.Eric Topol (17:38):Now I mean it is an amazing technology in all these years where we just were basically indiscriminately trying to kill cells and hoping that the cancer would succumb. And now you're finding whether you want to call it a carry or vector or Trojan horse, whatever you want to call it, but do you see that analogy of the HER2 receptor that's going to be seen across the board in other cancers?Charles Swanton (18:02):That's the big question, Eric. I think, and have we just lucked out with T-DXd, will we find other T-DXd like ADCs targeting other proteins? I mean there are a lot of ADCs being developed against a lot of different cell surface proteins, and I think the jury's still out. I'm confident we will, but we have to bear in mind that biology is a fickle friend and there may be something here related to the internalization of the receptor in breast cancer that makes this disease so exquisitely sensitive. So I think we just don't know yet. I'm reasonably confident that we will find other targets that are as profoundly sensitive as HER2 positive breast cancer, but time will tell.Cancer, A Systemic DiseaseEric Topol (18:49):Right. Now along these lines, well the recent paper that you had in Cell, called embracing cancer complexity, which we've talking about a bit, in fact it's kind of those two words go together awfully well, but hallmarks of systemic disease, this was a masterful review, as you say with the team that you led. But can you tell us about what's your main perspective about this systemic disease? I mean obviously there's been the cancer is like cardiovascular and cancers like this or that, but here you really brought it together with systemic illness. What can you say about that?Charles Swanton (19:42):Well, thanks for the question first of all, Eric. So a lot of this comes from some of my medical experience of treating cancer and thinking to myself over the years, molecular biology has had a major footprint on advances in treating the disease undoubtedly. But there are still aspects of medicine where molecular biology has had very little impact, and often that is in areas of suffering in patients with advanced disease and cancer related to things like cancer cachexia, thrombophilia. What is the reason why patients die blood clots? What is the reason patients die of cancer at all? Even a simple question like that, we don't always know the answer to, on death certificates, we write metastatic disease as a cause of cancer death, but we have patients who die with often limited disease burden and no obvious proximal cause of death sometimes. And that's very perplexing, and we need to understand that process better.(20:41):And we need to understand aspects like cancer pain, for example, circadian rhythms affect biological sensitivity of cancer cells to drugs and what have you. Thinking about cancer rather than just sort of a single group of chaotically proliferating cells to a vision of cancer interacting both locally within a microenvironment but more distantly across organs and how organs communicate with the cancer through neuronal networks, for example, I think is going to be the next big challenge by setting the field over the next decade or two. And I think then thinking about more broadly what I mean by embracing complexity, I think some of that relates to the limitations of the model systems we use, trying to understand inter-organ crosstalk, some of the things you cover in your beautiful Twitter reviews. (←Ground Truths link) I remember recently you highlighted four publications that looked at central nervous system, immune cell crosstalk or central nervous system microbiome crosstalk. It's this sort of long range interaction between organs, between the central nervous system and the immune system and the cancer that I'm hugely interested in because I really think there are vital clues there that will unlock new targets that will enable us to control cancers more effectively if we just understood these complex networks better and had more sophisticated animal model systems to be able to interpret these interactions.Eric Topol (22:11):No, it's so important what you're bringing out, the mysteries that still we have to deal with cancer, why patients have all these issues or dying without really knowing what's happened no less, as you say, these new connects that are being discovered at a remarkable pace, as you mentioned, that ground truths. And also, for example, when I spoke with Michelle Monje, she's amazing on the cancer, where hijacking the brain cells and just pretty extraordinary things. Now that gets me to another line of work of yours. I mean there are many, but the issue of evolution of the tumor, and if you could put that in context, a hot area that's helping us elucidate these mechanisms is known as spatial omics or spatial biology. This whole idea of being able to get the spatial temporal progression through single cell sequencing and single cell nuclei, all the single cell omics. So if you could kind of take us through what have we learned with this technique and spatial omics that now has changed or illuminated our understanding of how cancer evolves?Charles Swanton (23:37):Yeah, great question. Well, I mean I think it helps us sort of rewind a bit and think about evolution in general. Genetic selection brought about by diverse environments and environmental pressures that force evolution, genetic evolution, and speciation down certain evolutionary roots. And I think one can think about cancers in a similar way. They start from a single cell and we can trace the evolutionary paths of cancers by single cell analysis as well as bulk sequencing of spatially separated tumor regions to be able to reconstruct their subclones. And that's taught us to some extent, what are the early events in tumor evolution? What are the biological mechanisms driving branched evolution? How does genome instability begin in tumors? And we found through TRACERx work, whole genome doubling is a major route through to driving chromosome instability along with mutagenic enzymes like APOBEC that drive both mutations and chromosomal instability.(24:44):And then that leads to a sort of adaptive radiation in a sense, not dissimilar to I guess the Cambrian explosion of evolutionary opportunity upon which natural selection can act. And that's when you start to see the hallmarks of immune evasion like loss of HLA, the immune recognition molecules that bind the neoantigens or even loss of the neoantigens altogether or mutation of beta 2 microglobulin that allow the tumor cells to now evolve below the radar, so to speak. But you allude to the sort of spatial technologies that allow us to start to interpret the microenvironments as well. And that then tells us what the evolutionary pressures are upon the tumor. And we're learning from those spatial technologies that these environments are incredibly diverse, actually interestingly seem to be converging on one important aspect I'd like to talk to you a little bit more about, which is the myeloid axis, which is these neutrophils, macrophages, et cetera, that seem to be associated with poor outcome and that will perhaps talk about pollution in a minute.(25:51):But I think they're creating a sort of chronic inflammatory response that allows these early nascent tumor cells to start to initiate into frankly tumor invasive cells and start to grow. And so, what we're seeing from these spatial technologies in lung cancer is that T-cells, predatory T-cells, force tumors to lose their HLA molecules and what have you to evade the immune system. But for reasons we don't understand, high neutrophil infiltration seems to be associated with poor outcome, poor metastasis free survival. And actually, those same neutrophils we've recently found actually even tracked to the metastasis sites of metastasis. So it's almost like this sort of symbiosis between the myeloid cells and the tumor cells in their biology and growth and progression of the tumor cells.Eric Topol (26:46):Yeah, I mean this white cell story, this seems to be getting legs and is relatively new, was this cracked because of the ability to do this type of work to in the past everything was, oh, it's cancer's heterogeneous and now we're getting pinpoint definition of what's going on.Charles Swanton (27:04):I think it's certainly contributed, but it's like everything in science, Eric, when you look back, there's evidence in the literature for pretty much everything we've ever discovered. You just need to put the pieces together. And I mean one example would be the neutrophil lymphocyte ratio in the blood as a hallmark of outcome in cancers and to checkpoint inhibitor blockade, maybe this begins to explain it, high neutrophils, immune suppressive environment, high neutrophils, high macrophages, high immune suppression, less benefit from checkpoint inhibitor therapy, whereas you want lymphocyte. So I think there are biomedical medical insights that help inform the biology we do in the lab that have been known for decades or more. And certainly the myeloid M2 axis in macrophages and what have you was known about way before these spatial technologies really came to fruition, I think.The Impact of Air PollutionEric Topol (28:01):Yeah. Well you touched on this about air pollution and that's another dimension of the work that you and your team have done. As you well know, there was a recent global burden of disease paper in the Lancet, which has now said that air pollution with particulate matter 2.5 less is the leading cause of the burden of disease in the world now.Charles Swanton (28:32):What did you think of that, Eric?Eric Topol (28:34):I mean, I was blown away. Totally blown away. And this is an era you've really worked on. So can you put it in perspective?Charles Swanton (28:42):Yeah. So we got into this because patients of mine, and many of my colleagues would ask the same question, I've never smoked doctor, I'm healthy. I'm in my mid 50s though they're often female and I've got lung cancer. Why is that doctor? I've had a good diet, I exercise, et cetera. And we didn't really have a very good answer for that, and I don't want to pretend for a minute we solved the whole problem. I think hopefully we've contributed to a little bit of understanding of why this may happen. But that aside, we knew that there were risk factors associated with lung cancer that included air pollution, radon exposure, of course, germline genetics, we mustn't forget very important germline variation. And I think there is evidence that all of them are associated with lung cancer risk in different ways. But we wanted to look at air pollution, particularly because there was an awful lot of evidence, several meta-analysis of over half a million individuals showing very convincingly with highly significant results that increasing PM 2.5 micron particulate levels were associated with increased risk of lung cancer.(29:59):To put that into perspective, where you are on the west coast of the US, it's relatively unpolluted. You would be talking about maybe five micrograms per meter cubed of PM2.5 in a place like San Diego or Western California, assuming there aren't any forest fires of course. And we estimate that that would translate to about, we think it's about one extra case of never smoking lung cancer per hundred thousand of the population per year per one microgram per meter cube rise in the pollution levels. So if you go to Beijing for example, on a bad day, the air pollution levels could be upwards of a hundred micrograms per meter cubed because there are so many coal fired power stations in China partly. And there I think the risk is considerably higher. And that's certainly what we've seen in the meta-analyses in our limited and relatively crude epidemiological analyses to be the case.(30:59):So I think the association was pretty certain, we were very confident from people's prior publications  this was important. But of course, association is not causation. So we took a number of animal models and showed that you could promote lung cancer formation in four different oncogene driven lung cancer models. And then the question is how, does air pollution stimulate mutations, which is what I initially thought it would do or something else. It turns out we don't see a significant increase in exogenous like C to A carcinogenic mutations. So that made us put our thinking caps on. And I said to you earlier, often all these discoveries have been made before. Well, Berenblum in 1947, first postulated that actually tumors are initiated through a two-step process, which we now know involves a sort of pre initiated cell with a mutation in that in itself is not sufficient to cause cancer.(31:58):But on top of that you need an inflammatory stimulus. So the question was then, well, okay, is inflammation working here? And we found that there was an interleukin-1 beta axis. And what happens is that the macrophages come into the lung on pollution exposure, engulf phagocytose the air pollutants, and we think what's happening is the air pollutants are puncturing membranes in the lung. That's what we think is happening. And interleukin-1 beta preformed IL-1 beta is being released into the extracellular matrix and then stimulating pre-initiated cells stem cells like the AT2 cells with an activating EGFR mutation to form a tumor. But the EGFR mutation alone is not sufficient to form tumors. It's only when you have the interleukin-1 beta and the activated mutation that a tumor can start.(32:49):And we found that if we sequence normal lung tissue in a healthy adult 60-year-old adult, we will find about half of biopsies will have an activating KRAS mutation in normal tissue, and about 15% will have an activating mutation in EGFR in histologically normal tissue with nerve and of cancer. In fact, my friend and colleague who's a co-author on the paper, James DeGregori, who you should speak to in Colorado, fascinating evolutionary cancer biologists estimates that in a healthy 60-year-old, there are a hundred billion cells in your body that harbor an oncogenic mutation. So that tells you that at the cellular level, cancer is an incredibly rare event and almost never happens. I mean, our lifetime risk of cancer is perhaps one in two. You covered that beautiful pancreas paper recently where they estimated that there may be 80 to 100 KRAS mutations in a normal adult pancreas, and yet our lifetime risk of pancreas cancer is one in 70. So this tells you that oncogenic mutations are rarely sufficient to drive cancer, so something else must be happening. And in the context of air pollution associated lung cancer, we think that's inflammation driven by these white cells, these myeloid cells, the macrophages.Cancer BiomarkersEric Topol (34:06):No, it makes a lot of sense. And this, you mentioned the pancreas paper and also what's going in the lung, and it seems like we have this burden of all you need is a tipping point and air pollution seems to qualify, and you seem to be really in the process of icing the mechanism. And like I would've thought it was just mutagenic and it's not so simple, right? But that gets me to this is such an important aspect of cancer, the fact that we harbor these kind of preconditions. And would you think that cancer takes decades to actually manifest most cancers, or do we really have an opportunity here to be able to track whether it's through blood or other biomarkers? Another area you've worked on a lot whereby let's say you could define people at risk for polygenic risk scores or various cancers or genome sequencing for predisposition genes, whatever, and you could monitor in the future over the course of those high-risk people, whether they were starting to manifest microscopic malignancy. Do you have any thoughts about how long it takes for the average person to actually manifest a typical cancer?Charles Swanton (35:28):That's a cracking question, and the answer is we've got some clues in various cancers. Peter Campbell would be a good person to speak to. He estimates that some of the earliest steps in renal cancer can occur in adolescence. We've had patients who gave up smoking 30 or so years ago where we can still see the clonal smoking mutations in the trunk of the tumor's evolutionary tree. So the initial footprints of the cancer are made 30 years before the cancer presents. That driver mutation itself may also be a KRAS mutation in a smoking cigarette context, G12C mutation. And those mutations can precede the diagnosis of the disease by decades. So the earliest steps in cancer evolution can occur, we think can precede diagnoses by a long time. So to your point, your question which is, is there an opportunity to intervene? I'm hugely optimistic about this actually, this idea of molecular cancer prevention.An Anti-Inflammatory Drug Reduces Fatal Cancer and Lung Cancer(36:41):How can we use data coming out of various studies in the pancreas, mesothelioma, lung, et cetera to understand the inflammatory responses? I don't think we can do very much about the mutations. The mutations unfortunately are a natural consequence of aging. You and I just sitting here talking for an hour will have accumulated multiple mutations in our bodies over that period, I'm afraid and there's no escaping it. And right now there's not much we can do to eradicate those mutant clones. So if we take that as almost an intractable problem, measuring them is hard enough, eradicating them is even harder. And then we go back to Berenblum in 1947 who said, you need an inflammatory stimulus. Well, could we do something about the inflammation and dampen down the inflammation? And of course, this is why we got so excited about IL-1 beta because of the CANTOS trial, which you may remember in 2017 from Ridker and colleagues showed that anti IL-1 beta used as a mechanism of preventing cardiovascular events was associated with a really impressive dose dependent reduction in new lung cancer primaries.(37:49):Really a beautiful example of cancer prevention in action. And that data weren't just a coincidence. The FDA mandated Novartis to collect the solid tumor data and the P-values are 0.001. I mean it's very highly significant dose dependent reduction in lung cancer incidents associated with anti IL-1 beta. So I think that's really the first clue in my mind that something can be done about this problem. And actually they had five years of follow-up, Eric. So that's something about that intervening period where you can treat and then over time see a reduction in new lung cancers forming. So I definitely think there's a window of opportunity here.Eric Topol (38:31):Well, what you're bringing up is fascinating here because this trial, which was a cardiology trial to try to reduce heart attacks, finds a reduction in cancer, and it's been lost. It's been buried. I mean, no one's using this therapy to prevent cancer between ratcheting up the immune system or decreasing inflammation. We have opportunities that we're not even attempting. Are there any trials that are trying to do this sort of thing?Charles Swanton (39:02):So this is the fundamental problem. Nobody wants to invest in prevention because essentially you are dealing with well individuals. It's like the vaccine challenge all over again. And the problem is you never know who you are benefiting. There's no economic model for it. So pharma just won't touch prevention with a barge pole right now. And that's the problem. There's no economic model for it. And yet the community, all my academic colleagues are crying out saying, this has got to be possible. This has got to be possible. So CRUK are putting together a group of like-minded individuals to see if we can do something here and we're gradually making progress, but it is tough.Eric Topol (39:43):And it's interesting that you bring that up because for GRAIL, one of the multicenter cancer early detection companies, they raised billions of dollars. And in fact, their largest trial is ongoing in the UK, but they haven't really focused on high-risk people. They just took anybody over age 50 or that sort of thing. But that's the only foray to try to reboot how we or make an early microscopic diagnosis of cancer and track people differently. And there's an opportunity there. You've written quite a bit on you and colleagues of the blood markers being able to find a cancer where well before, in fact, I was going to ask you about that is, do you think there's people that are not just having all these mutations every minute, every hour, but that are starting to have the early seeds of cancer, but because their immune system then subsequently kicks in that they basically kind of quash it for that period of time?Charles Swanton (40:47):Yeah, I do think that, I mean, the very fact that we see these sort of footprints in the tumor genome of immune evasion tells you that the immune system's having a very profound predatory effect on evolving tumors. So I do think it's very likely that there are tumors occurring that are suppressed by the immune system. There is a clear signature, a signal of negative selection in tumors where clones have been purified during their evolution by the immune system. So I think there's pretty strong evidence for that now. Obviously, it's very difficult to prove something existed when it doesn't now exist, but there absolutely is evidence for that. I think it raises the interesting question of immune system recognizes mutations and our bodies are replete with mutations as we were just discussing. Why is it that we're not just a sort of epithelial lining of autoimmunity with T-cells and immune cells everywhere? And I think what the clever thing about the immune system is it's evolved to target antigens only when they get above a certain burden. Otherwise, I think our epithelial lining, our skin, our guts, all of our tissues will be just full of T-cells eating away our normal clones.(42:09):These have to get to a certain size for antigen to be presented at a certain level for the immune system to recognize it. And it's only then that you get the immune predation occurring.Forever Chemicals and Microplastics Eric Topol (42:20):Yeah, well, I mean this is opportunities galore here. I also wanted to extend the air pollution story a bit. Obviously, we talked about particulate matter and there's ozone and nitric NO2, and there's all sorts of other air pollutants, but then there's also in the air and water these forever chemicals PFAS for abbreviation, and they seem to be incriminated like air pollution. Can you comment about that?Charles Swanton (42:55):Well, I can comment only insofar as to say I'm worried about the situation. Indeed, I'm worried about microplastics actually, and you actually cover that story as well in the New England Journal, the association of microplastics with plaque rupture and atheroma. And indeed, just as in parenthesis, I wanted to just quickly say we currently think the same mechanisms that are driving lung cancer are probably responsible for atheroma and possibly even neurodegenerative disease. And essentially it all comes down to the macrophages and the microglia becoming clogged up with these pollutants or environmental particulars and releasing chronic inflammatory mediators that ultimately lead to disease. And IL-1 beta being one of those in atheroma and probably IL-6 and TNF in neurodegenerative disease and what have you. But I think this issue that you rightly bring up of what is in our environment and how does it cause pathology is really something that epidemiologists have spent a lot of time focusing on.(43:56):But actually in terms of trying to move from association to causation, we've been, I would argue a little bit slow biologically in trying to understand these issues. And I think that is a concern. I mean, to give you an example, Allan Balmain, who works at UCSF quite close to you, published a paper in 2020 showing that 17 out of 20 environmental carcinogens IARC carcinogens class one carcinogens cause tumors in rodent models without driving mutations. So if you take that to a logical conclusion, in my mind, what worries me is that many of the sort of carcinogen assays are based on driving mutagenesis genome instability. But if many carcinogen aren't driving DNA mutagenesis but are still driving cancer, how are they doing it? And do we actually have the right assays to interpret safety of new chemical matter that's being introduced into our environment, these long-lived particles that we're breathing in plastics, pollutants, you name it, until we have the right biological assays, deeming something to be safe I think is tricky.Eric Topol (45:11):Absolutely. And I share your concerns on the nanoplastic microplastic story, as you well know, not only have they been seen in arteries that are inflamed and in blood clots and in various tissues, have they been seen so far or even looked for within tumor tissue?Charles Swanton (45:33):Good question. I'm not sure they have. I need to check. What I can tell you is we've been doing some experiments in the lab with fluorescent microplastics, 2.5 micron microplastics given inhaled microplastics. We find them in every mouse organ a week after. And these pollutants even get through into the brain through the olfactory bulb we think.Charles Swanton (45:57):Permeate every tissue, Eric.Eric Topol (45:59):Yeah, no, this is scary because here we are, we have these potentially ingenious ways to prevent cancer in the future, but we're chasing our tails by not doing anything to deal with our environment.Charles Swanton (46:11):I think that's right. I totally agree. Yeah.Eric Topol (46:15):So I mean, I can talk to you for the rest of the day, but I do want to end up with a topic that we have mutual interest in, which is AI. And also along with that, when you mentioned about aging, I'd like to get your views on these two, how do you see AI fitting into the future of cancer? And then the more general topic is, can we actually at some point modulate the biologic aging process with or without help with from AI? So those are two very dense questions, but maybe you can take us through them.Charles Swanton (46:57):How long have we got?Eric Topol (46:59):Just however long you have.A.I. and CancerCharles Swanton (47:02):AI and cancer. Well, AI and medicine actually in general, whether it's biomedical research or medical care, has just infinite potential. And I'm very, very excited about it. I think what excites me about AI is it's almost the infinite possibilities to work across scale. Some of the challenges we raised in the Cell review that you mentioned, tackling, embracing complexity are perfectly suited for an AI problem. Nonlinear data working, for instance in our fields with CT imaging, MRI imaging, clinical outcome data, blood parameters, genomics, transcriptomes and proteomes and trying to relate this all into something that's understandable that relates to risk of disease or potential identification of a new drug target, for example. There are numerous publications that you and others have covered that allude to the incredible possibilities there that are leading to, for instance, the new identification of drug targets. I mean, Eli Van Allen's published some beautiful work here and in the context of prostate cancer with MDM4 and FGF receptor molecules being intimately related to disease biology.(48:18):But then it's not just that, not just drug target identification, it's also going all the way through to the clinic through drug discovery. It's how you get these small molecules to interact with oncogenic proteins and to inhibit them. And there are some really spectacular developments going on in, for instance, time resolved cryo-electron microscopy, where in combination with modeling and quantum computing and what have you, you can start to find pockets emerging in mutant proteins, but not the wild type ones that are druggable. And then you can use sort of synthetic AI driven libraries to find small molecules that will be predicted to bind these transiently emerging pockets. So it's almost like AI is primed to help at every stage in scientific investigation from the bench all the way through to the bedside. And there are examples all the way through there in the literature that you and others have covered in the last few years. So I could not be more excited about that.Eric Topol (49:29):I couldn't agree with you more. And I think when we get to multimodal AI at the individual level across all their risks for conditions in their future, I hope someday will fulfill that fantasy of primary prevention. And that is getting me to this point that I touched on because I do think they interact to some degree AI and then will we ever be able to have an impact on aging? Most people conflate this because what we've been talking about throughout the hour has been age-related diseases, that is cancer, for example, and cardiovascular and neurodegenerative, which is different than changing aging per se, body wide aging. Do you think we'll ever changed body wide aging?Charles Swanton (50:18):Wow, what a question. Well, if you'd asked me 10 years ago, 15 years ago, do you think we'll ever cure melanoma in my lifetime, I'd have said definitely not. And now look where we are. Half of patients with melanoma, advanced melanoma, even with brain metastasis curd with combination checkpoint therapy. So I never say never in biology anymore. It always comes back to bite you and prove you wrong. So I think it's perfectly possible.Charles Swanton (50:49):We have ways to slow down the aging process. I guess the question is what will be the consequences of that?Eric Topol (50:55):That's what I was going to ask you, because all these things like epigenetic reprogramming and senolytic drugs, and they seem to at least pose some risk for cancer.Charles Swanton (51:09):That's the problem. This is an evolutionary phenomenon. It's a sort of biological response to the onslaught of these malignant cells that are potentially occurring every day in our normal tissue. And so, by tackling one problem, do we create another? And I think that's going to be the big challenge over the next 50 years.Eric Topol (51:31):Yeah, and I think your point about the multi-decade challenge, because if you can promote healthy aging without any risk of cancer, that would be great. But if the tradeoff is close, it's not going to be very favorable. That seems to be the main liability of modulation aging through many of the, there's many shots on goal here, of course, as you well know. But they do seem to pose that risk in general.Charles Swanton (51:58):I think that's right. I think the other thing is, I still find, I don't know if you agree with me, but it is an immense conundrum. What is the underlying molecular basis for somatic aging, for aging of normal tissues? And it may be multifactorial, it may not be just one answer to that question. And different tissues may age in different ways. I don't know. It's a fascinating area of biology, but I think it really needs to be studied more because as you say, it underpins all of these diseases we've been talking about today, cardiovascular, neurodegeneration, cancer, you name it. We absolutely have to understand this. And actually, the more I work in cancer, the more I feel like actually what I'm working on is aging.(52:48):And this is something that James DeGregori and I have discussed a lot. There's an observation that in medicine around patients with alpha-1 antitrypsin deficiency who are at higher risk of lung cancer, but they're also at high risk of COPD, and we know the associations of chronic obstructive pulmonary disease with lung cancer risk. And one of the theories that James had, and I think this is a beautiful idea, actually, is as our tissues age, and COPD is a reflection of aging, to some extent gone wrong. And as our tissues age, they become less good at controlling the expansion of these premalignant clones, harboring, harboring oncogenic mutations in normal tissue. And as those premalignant clones expand, the substrate for evolution also expands. So there's more likely to be a second and third hit genetically. So it may be by disrupting the extracellular matrices through inflammation that triggers COPD through alpha-1 antitrypsin deficiency or smoking, et cetera, you are less effectively controlling these emergent clones that just expand with age, which I think is a fascinating idea actually.Eric Topol (54:01):It really is. Well, I want to tell you, Charlie, this has been the most fascinating, exhilarating discussion I've ever had on cancer. I mean, really, I am indebted to you because not just all the work you've done, but your ability to really express it, articulate it in a way that hopefully everyone can understand who's listening or reading the transcript. So we'll keep following what you're doing because you're doing a lot of stuff. I can't thank you enough for joining me today, and you've given me lots of things to think about. I hope the people that are listening or reading feel the same way. I mean, this has been so mind bending in many respects. We're indebted to you.Charles Swanton (54:49):Well, we all love reading your Twitter feeds. Keep them coming. It helps us keep a broader view of medicine and biological research, not just cancer, which is why I love it so much.******************************************The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff tor audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

Neurology Minute
Neurologic Clinical Features of Patients With CTLA4 Deficiency

Neurology Minute

Play Episode Listen Later Feb 15, 2024 2:15


Dr. Justin Abbatemarco and Prof. Xavier Ayrignac discuss the importance of considering alternative diagnoses for CTLA4 deficiencies.  Show reference: https://www.neurology.org/doi/10.1212/wnl.0000000000207609

Neurology® Podcast
Neurologic Clinical Features of Patients With CTLA4 Deficiency

Neurology® Podcast

Play Episode Listen Later Feb 12, 2024 14:39


Dr. Justin Abbatemarco talks with Prof. Xavier Ayrignac about the importance of considering alternative diagnoses for CTLA4 deficiencies.  Read the related article in Neurology.

Beyond Biotech - the podcast from Labiotech
Beyond Biotech podcast 64 – Precision immuno-oncology therapies

Beyond Biotech - the podcast from Labiotech

Play Episode Listen Later Sep 22, 2023 38:31


Despite the huge commercial success of PD-1 inhibitors and widespread use of checkpoint inhibitors such as anti-PD-1 or anti-CTLA4, 70 to 80% of patients still experience limited or no response to existing therapies.  In response to this critical challenge, Portage Biotech is on a mission to expand the number of patients who derive long-term benefits from immunotherapies.  Portage Biotech is advancing a portfolio of novel precision immuno-oncology therapies, including invariant natural killer T-cell (iNKT) engagers, designed to correct the tumor microenvironment and enable the body to recognize and attack tumors, and next-generation adenosine inhibitors for a variety of cancers, with better potency, selectivity and durability. Heading this pioneering endeavor is Dr. Ian Walters, Portage's CEO, who brings decades of experience in the immuno-oncology space. With a unique background as a physician with a business degree, Dr. Walters has been deeply involved in academia and large pharmaceutical companies. He played a pivotal role in the development of some of the first checkpoint inhibitors and has supported the approval of five oncology drugs.  In this conversation, Walters tells Labiotech about Portage's unique approach to targeting known checkpoint resistant pathways and the company's strategy to revolutionize immunotherapy research and drug development.

Cancer.Net Podcasts
2023 Research Round Up: Melanoma and Health Equity

Cancer.Net Podcasts

Play Episode Listen Later Sep 12, 2023 22:05


ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. The theme of the 2023 ASCO Annual Meeting was “Partnering With Patients: The Cornerstone of Cancer Care and Research.” From June 2 to 6 in Chicago, Illinois, and online, cancer researchers and clinicians from around the world gathered to discuss the latest cancer research and how to ensure that all people receive the cancer care they need. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field presented at the meeting and explain what it means for people with cancer. In today's episode, our guests will discuss new research in melanoma and health equity. First, Dr. Katy Tsai discusses new research in melanoma. Dr. Tsai is a medical oncologist and Assistant Professor of Medicine in the Division of Hematology and Oncology at the University of California, San Francisco. She is also the 2023 Cancer.Net Associate Editor for Melanoma & Skin Cancer. You can view Dr. Tsai's disclosures at Cancer.Net. Dr. Tsai: Hello. Welcome to the ASCO Cancer.Net Research Round Up. I'm Katy Tsai, an associate professor of medicine and the clinical medical director of the Melanoma and Skin Cancer Program at the University of California, San Francisco. I'm happy to be here today to discuss research on melanoma and skin cancers presented at the 2023 ASCO Annual Meeting. I do not have any disclosures relevant to the studies to be discussed. So, it's always exciting to see the latest research presented at ASCO. One theme in particular that I'd like to highlight in this podcast is recent advances in the field of adjuvant therapy. For the listeners who may not be familiar with this terminology, adjuvant therapy refers to drugs given after surgery to try to decrease the risk of cancer recurrence. Specifically, late-breaking abstract 9505 presented updates from KEYNOTE-716, an adjuvant study of pembrolizumab, or pembro, in patients with resected high-risk stage II melanoma. Late-breaking abstract 9503, which I'll also discuss, presented data from KEYNOTE-942, a pivotal study of a personalized cancer vaccine plus pembrolizumab in patients with resected high-risk stage III and stage IV melanoma. So, let's start with KEYNOTE-716. We've known for some time in our field now that adjuvant pembrolizumab or nivolumab can help decrease the risk of recurrence for patients with resected stage III or IV melanoma. What may not be as well-known, however, is that patients with stage IIB or IIC melanomas, in other words, thicker, ulcerated primary melanomas, even without lymph node spread, actually have a comparable risk of melanoma recurrence compared to patients with early stage III melanomas. KEYNOTE-716 was a large, international phase 3 study that randomized patients with stages IIB and C melanoma to receive either pembro or placebo. The positive results showing improvement in relapse-free survival led to approval of adjuvant pembro in December 2021, but what was presented at ASCO was an update on distant metastasis-free survival. This is obviously an important endpoint for us because ultimately, if someone is going to develop widely metastatic disease, unfortunately, it is a development of these distant metastases that we are concerned about. So what we saw here is that with landmark 36-month follow-up, there was a 41% reduction in the risk of developing distant metastasis in patients who were treated with pembro compared to those who received the placebo. In addition, there was a consistent maintained benefit in relapse-free survival, and importantly, no changes in the side effect profile. These are important data because I believe it is practice-changing in the sense that this is a population of patients who historically might not ever have been referred to medical oncology, maybe just monitored serially with their dermatologists. And this is an option that should be discussed. Ultimately, the risk versus benefit about whether to pursue a year of therapy versus maybe consider treatment only at the time of recurrence is a very personalized discussion between a patient and their treating oncologist, but it is an option that should definitely be offered. So let's move on to KEYNOTE-942. The novel drug being tested in this trial is very exciting. We're calling it “individualized neoantigen therapy.” So this is basically a platform that allows us to develop individualized treatment for someone based on characteristics of their own cancer. This involves taking the actual tumor specimen, genomic sequencing, specifically whole-exome sequencing is performed to try to identify any changes in the DNA. And then through a bioinformatic pipeline, the mutations in the DNA that are thought to be most likely to generate proteins that can be bound within presenting molecules are then identified in the computer program, then synthesized within mRNA. So very similar to the way that COVID vaccines have been made. So this actually becomes the actual drug product. So in this study, patients were randomized to receive either pembrolizumab by itself for a year, which is, as we alluded to earlier, standard adjuvant therapy, but then with the addition of this individualized neoantigen therapy starting with dose 3 and then throughout the rest of the year. So the recurrence-free survival data were actually presented earlier this year at another major conference, AACR [American Association for Cancer Research], and were highly positive. At ASCO 2023, I think what was most impressive about the presented data is that distant metastasis-free survival, so again, a similar important endpoint that we discussed with the other trial, is that the distant metastasis-free survival here was quite impressively maintained. There was a hazard ratio of .35, meaning really a 65% reduction in the risk of recurrence for patients who received the personalized neoantigen therapy plus pembrolizumab. So this is a huge advantage for distant metastasis-free survival in this particular population of patients. What was even more intriguing is that usually when we combine therapies, we tend to see additive toxicity, more side effects. And what was really exciting about this particular trial is that the additive toxicity really wasn't as much as you would expect for giving 2 immunotherapies at the same time. I'll also highlight that even though these results are really exciting within melanoma, that part of the reason this data is so exciting is that it represents a really promising platform for therapeutic development and application in other tumors besides melanoma. So this is definitely super exciting. While perhaps not practice-changing in this moment, it's potentially practice-changing. And I look forward to seeing additional data coming in from planned trials using this particular combination in the metastatic setting in addition to the adjuvant setting. So on the whole, I do think that updates in adjuvant therapy for melanoma were super exciting to see at ASCO 2023. As I mentioned earlier, it's a very large conference. A lot of exciting data being presented. So I do think that other themes to pay attention to as we continue to sort through existing data and look forward to incoming data from forthcoming trials is looking at neoadjuvant therapy. For example, drug given before surgery to try to improve long-term outcomes. For example, at ASCO this year, there was interesting neoadjuvant immunotherapy data presented not for melanoma, but for a different type of skin cancer called squamous cell carcinoma. So that would definitely be another theme to pay attention to in the coming months and years. Thinking about novel combinations, for example, what's new in immune checkpoint inhibitors, we've been used to for a long time referring only to anti-PD1 antibodies, anti-CTLA4 antibodies. What was interesting to see this year were updates in novel combinations, for example, PD1 antibodies combined with LAG3 antibodies. Antibodies against TIGIT. So I think this will be another exciting space to pay attention to both in the metastatic skin cancer setting and in the adjuvant and neoadjuvant settings. Thank you for your time and attention. That concludes my research roundup for melanoma and skin cancers. Thank you. ASCO: Thank you, Dr. Tsai. Next, Dr. Manali Patel discusses new research in health equity. Dr. Patel is a medical oncologist and Assistant Professor of Medicine at Stanford University. She is also the 2023 Cancer.Net Associate Editor for Health Equity. You can view Dr. Patel's disclosures at Cancer.Net. Dr. Patel: Hi, my name is Manali Patel. I'm the Associate Editor for Health Equity for Cancer.Net, and I'm so incredibly excited to present some really amazing work that was presented at our ASCO Annual Meeting this past June in Chicago. Before I start, I do have one disclosure. I will be talking about studies that were presented relating to patient navigation and one study in particular that my group presented looking at community health workers. And so that is a little bit of a disclosure that I would like to address upfront. And now, just to get right started. I thought what was really interesting was the amount of work this year that was presented on disparities in health equity. As in past years, we actually saw quite an influx, probably more so this year than previously, on studies that looked at differing outcomes, inequities in cancer care delivery, describing disparities in terms of receipt of treatment, so if people were receiving treatment. There tended to be a lot of studies that focused on looking at and describing a lot of these disparities. But what I was really impressed by came out from the pediatric colleagues, individuals who are taking care of younger patients, children who are less than the age of 18, and how many of those particular studies were focused on moving from description to actually intervening and making a difference in health equity. And so I want to highlight a couple. There was one that was done out of Dana-Farber, and actually, a multi-site group of authors. So lots of authors from all over the place, but Emily Jones was the lead author. And they described and actually evaluated how they could collect, in the context of clinical trials for children, which is called Children's Oncology Group Trial-- how they could collect social determinants of health data, meaning data that evaluates people's income, transportation, where people live, what kind of work they may do, if they have food and housing insecurity. And what they were able to show is that, by embedding a lot of these data points-- they actually made these data points optional for patients when they came into the clinical trial. And they found high feasibility, meaning lots of people that were signing up to do clinical trials for the Children's Oncology Group Trial were able to complete this extra data, which is extremely important and is a remarkable willingness of individuals to participate in providing this data which is important for their treatment. Along those same lines, Amy Newman from the Children's Hospital of Philadelphia really did a very nice study looking at the feasibility of what they called PediCARE. And it was this intervention that was focused on trying to ensure that people-- again, children less than the age of 18 across 2 different clinics. They evaluated whether PediCARE would help people to receive necessary and important resources as it relates to social and economic needs. And so they screened for food insecurity, for housing insecurity, for people that had difficulties paying for utilities, and transportation security. And then they randomized individuals to either PediCARE or to just usual cancer care. And what they found was that 100% of the people that were randomized to PediCARE successfully received grocery and transportation resources. They felt that it was easier to buy food for their family, and they reported it was easier to get to and from the hospital and that they would be very likely to report and to recommend this intervention to other individuals. And so it really shows how these interventions can move from just describing that housing, food insecurity or problems-- number 1, it starts with the collection of the data, right? What's really important is making sure that we collect this data because we don't currently do that in cancer care. And then number 2, when we actually do collect the data, what are we going to do about it? And it shows that these interventions really do help people to move past their housing and social and economic issues that they may experience into actually receiving care that's important and necessary to improve outcomes. We did see a lot of data reflecting the importance of health insurance and big policies, what I call Big P, which are these national policies, like the Affordable Care Act. And now we've seen, just year after year and including this year, plethora of studies showing how beneficial the Affordable Care Act has been on reducing disparities and improving cancer outcomes overall. We also saw other studies, such as one presented by Dr. Gladys Rodriguez from Northwestern, which looked at disparities in the intensity of care at the end of life amongst patients with gastrointestinal cancers. And the team revealed, across almost 20 years of data in California, that patients were receiving higher rates of what would be considered low-quality care. Now, this is lower hospice use, which we know helps to actually improve survival, lower rates of palliative care use, and greater rates of burdensome hospitalizations. And now, why I think this is particularly important is because this study evaluated what we know is a problem, that there is low-quality care amongst patients from particular racial and ethnic populations, such as Black and Hispanic patient populations, that aren't receiving the right care when they're diagnosed. And then what this reveals is that, even at the end of life, they're perhaps still receiving low-quality care. Another study looked at screening, which I thought was really impressive. It was by Nicole Anne Gay from the UM Sylvester Comprehensive Cancer Center in Miami. And what they evaluated was essentially a quality improvement program to reduce disparities in lung cancer screening. As a lung cancer doctor myself, it's still shocking that fewer than 6% of people that should receive lung cancer screening, meaning a screening test to help us identify and to treat patients with lung cancer-- they aren't receiving lung cancer screening. And so we know that this is a problem overall. They put into place what's called a multi-level, meaning that there were improvements in the electronic health record that they embedded. They also provided patients with navigation, and they also helped clinicians in the primary care clinics obtain information about who should be eligible and which patients should be receiving screening. And what they found was that they were able to move screening rates from 25% improvement completed during the project period from their baseline, which is actually quite impressive. We also saw an interesting study, and actually, just an interesting evaluation, of childhood leukemia survival on the U.S.-Mexico border. And it was a description of how to implement changes by strengthening care partnerships. And so they evaluated and they described the implementation of this program to achieve what they called sustainable high-quality care for children with leukemia. It was done by Paula Aristizabal and was really in a unique border health setting. It was in partnership between the North American and Mexican institutions. And they used what was called the strengthening model developed by the World Health Organization to evaluate specific domains and to try to improve a sustainable program for children with acute lymphoblastic leukemia at a public referral hospital right on the border region. And I thought that that study was particularly interesting because it shows how to be able to use an approach to improve the staffing of a leukemia service, to implement a sustainable training program as well for other clinicians to learn how to provide leukemia care, and then also to try to improve clinical outcomes and funding for patients to receive medications through local partnerships. I thought it was a really fantastic description of how to begin to do this work that is extremely necessary in low- and middle-income nations but also even on our own U.S.-Mexico border. There were also a lot of studies that evaluated the importance of social and economic factors. We know that financial toxicity, which is an unfortunate side effect of cancer treatment and cancer care and a cancer diagnosis overall, is associated with worse outcomes. Financial toxicity means the burdens and costs that arise with having a cancer diagnosis. And now we've seen studies that were presented at ASCO this past year by Dr. Khan, who showed that, within 2 years of diagnosis, are at higher risk for dying after adjusting for many social and also clinical factors. And Dr. Hu also presented data looking at the implications of having a lot of medical debt and death. And what both of these studies showed is that medical debt is associated with having perhaps a lower likelihood of surviving. It does make sense for Dr. Hu's study that one would have a lot of medical debt if they also have a lot of other conditions, but it does begin to shed some light on the fact that there are worse clinical outcomes, meaning people aren't doing as well, depending on how much other medical care expenses they may have. And then finally, one important piece, which I think is really crucial for what's happening now in the way that oncologists may perhaps be able to advocate for payment for services that are important, is looking at navigation studies. Now, this is patient navigators, and that is a very broad topic. And so there were lots and lots of studies that came out at ASCO that evaluated the importance of navigation, including our own work that looked at what happens to veterans after receiving a lay health worker or a navigator to assist with advanced care planning, meaning helping veterans to understand their goals and preferences. And what these studies have shown is that there's actually not only clinical benefit but also, in our own study, that perhaps there may be a survival benefit even 10 years later. It was very wonderful to be at ASCO this past year, and I really hope that you all can look at some of these studies or take away the important and amazing work that's going on in the health equity space. And I thank you for listening to our podcast. ASCO: Thank you, Dr. Patel. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate. [music]

Dr. Westin Childs Podcast: Thyroid | Weight loss | Hormones
How to Prevent Hashimoto's (The Genetics Connection)

Dr. Westin Childs Podcast: Thyroid | Weight loss | Hormones

Play Episode Listen Later May 30, 2023 11:46


Is Hashimoto's a genetic condition? The short answer is yes but what's key here is that just because you may have the underlying genetics associated with developing Hashimoto's doesn't guarantee that that the disease state will manifest in your body. And this is key. Understanding this genetic component will allow you to live your life in such a way as to avoid certain factors which have the potential to trigger Hashimoto's. This means you can either a) prevent Hashimoto's or b) treat your condition upstream if it's already present. The genes and endogenous factors associated with Hashimoto's include: - HLA class DR3 and DR5 (there are many others but these are most common) - CTLA4 receptor - PTN22 - Female sex - Pregnancy - Skewed X Chromosome inactivation These by themselves are not enough to trigger the disease, though, as they must be combined with exogenous or environmental factors as well. The environmental factors that trigger these genes include: - High-dose iodine exposure - Infections - Cytokines - Environmental toxicants like EDCs, heavy metals, and radiation The key here is not to focus on your genes because you can't change those but to instead focus on what sort of things you put your body into contact with. By controlling these environmental factors you can actually influence your risk of developing Hashimoto's in a positive way. #hashimoto #hashimotosthyroiditis #hashimotosdisease #hashimotos #thyroid #hypothyroidism #genetics Download my free thyroid resources here (including hypothyroid symptoms checklist, the complete list of thyroid lab tests + optimal ranges, foods you should avoid if you have thyroid disease, and more): https://www.restartmed.com/start-here/ Recommended thyroid supplements to enhance thyroid function: - Supplements that everyone with hypothyroidism needs: https://bit.ly/3tekPej - Supplement bundle to help reverse Hashimoto's: https://bit.ly/3gSY9eJ - Supplements for those without a thyroid and for those after RAI: https://bit.ly/3tb36nZ - Supplements for active hyperthyroidism: https://bit.ly/3t70yHo See ALL of my specialized supplements including protein powders, thyroid supplements, and weight loss products here: https://www.restartmed.com/shop/ Want more from my blog? I have more than 400+ well-researched blog posts on thyroid management, hormone balancing, weight loss, and more. See all blog posts here: https://www.restartmed.com/blog/ Prefer to listen via podcast? Download all of my podcast episodes here: https://apple.co/3kNYTCS Disclaimer: Dr. Westin Childs received his Doctor of Osteopathic Medicine from Rocky Vista University College of Osteopathic medicine in 2013. His use of “doctor” or “Dr.” in relation to himself solely refers to that degree. Dr. Childs is no longer practicing medicine and does not hold an active medical license so he can focus on helping people through videos, blog posts, research, and supplement formulation. To read more about why he is no longer licensed please see this page: https://www.restartmed.com/what-happened-to-my-medical-license/ This video is for general informational, educational, and entertainment purposes only. It should not be used to self-diagnose and it is not a substitute for a medical exam, treatment, diagnosis, prescription, or recommendation. It does not create a doctor-patient relationship between Dr. Childs and you. You should not make any changes to your medications or health regimens without first consulting a physician. If you have any questions please consult with your current primary care provider. Restart Medical LLC and Dr. Westin Childs are not liable or responsible for any advice, course of treatment, diagnosis, or any other information, services, or product you obtain through this website or video. #thyroid #hypothyroidism #hashimoto's

Aprendiendo del Experto
#11 Nuria Gago: Investigando sobre el Melanoma

Aprendiendo del Experto

Play Episode Listen Later Jun 9, 2022 78:54


La Dra Nuria Gago López forma parte del Grupo de Investigación sobre el Melanoma del Centro Nacional de Investigaciones Oncológicas (CNIO), Grupo dirigido por la Dra. Marisol Soengas. El melanoma es el tumor de piel más letal que existe y tiene una intensa relación con la exposición solar, habiendo aumentado en su incidencia en los últimos años. A pesar de su gravedad, este tumor puede ser curable si es diagnosticado y tratado en fases iniciales. Incluso en casos avanzados con metástasis, nuevos tratamientos de inmunoterapias y terapias dirigidas, han aumentado mucho la supervivencia de los pacientes. Estos avances se deben en gran parte a investigaciones y avances tecnológicos como la secuenciación del DNA tumoral, que ha permitido conocer las mutaciones que aparecen en este tumor, cómo se va desarrollando y como el organismo se defiende frente a las células tumorales del melanoma. En este episodio la Dra. Gago nos explica los cambios iniciales (mutaciones) que se han descubierto y que son las responsables de que una celula melanocítica normal se transforma en una célula cancerosa que comienza a proliferar de forma descontrolada dando lugar al melanoma, tumor que tiene gran avidez para diseminarse a otras partes del organismo. Con la Dra Nuria Gago charlamos tambien sobre la investigación en España y el papel de la mujer en la ciencia española. 00:00 Mis inicios. Tesis Doctoral Ander Izeta. USA Cardiologia Macllelan 04:00 CNIO. Psoriasis. Erwin Wagner. Grupo de Melanoma. Marisol Soengas 06:00 Melanoma: Introducción. Daño solar en el DNA del melanocito 09:30 Melanocitos en Folículos Pilosos. Melanoma cuero cabelludo. 14:30 Mutaciones. Clasificación molecular del Melanoma. BRAF, NRAS, NF1 24:30 El Sol como causa del cancer de piel 27:30 Los lunares (nevus) también tienen mutaciones. Melanocitos senescentes. 31:30 Estadios iniciales del Melanoma. Estrategias de estudio. 39:00 Microambiente. Sistema inmunológico. Neoantígenos. 45:00 Inmunoterapia. Proteinas PD1 y CTLA4. 49:30 Por que el melanoma metastatiza tanto y respuestas a la Inmunoterapia 53:00 Reflexiones sobre la Investigación en España y extranjero 58: 00 Hay que mejorar relación entre Centros de Investigación y la Universidad 1:02:00 Consejo al Investigador novel. 1:04:00 Hay que divulgar la ciencia. 1:06:00 La mujer y la Ciencia en España. Escasez en puestos directivos. 1:11:30 Mis aficiones: pintura y familia 1:12:30 Libros: Por mil millones de dólares. Vazquez-Figueroa 1:16:30 Países para viajar: España. Costa Californiana.

The Uromigos
Episode 140: What is the role of ipilimumab in renal cancer?

The Uromigos

Play Episode Listen Later Oct 29, 2021 25:18


Mike Atkins discusses the role of CTLA4 inhibition in RCC.

The Peer Med Podcast
Behind Diagnoses: Patients - E3: CTLA4 Haploinsufficiency ft. Samantha Gehrls

The Peer Med Podcast

Play Episode Listen Later Sep 29, 2021 30:52


On this episode of "Behind Diagnoses: Patients", a Peer Med Podcast special series we hear from Samantha Gehrls. She has been battling chronic illness for 5 years and her mission is to spread awareness about how life looks being ill. Sam has been diagnosed with Systemic Lupus (SLE), Lupus Nephritis (kidney disease), T1D, CTLA4 deficiency, Antiphospholipid Syndrome, Hashimoto's, & has a plethora of other ailments that have left her home bound for the past several years and even bed bound most days. She has yet to find a treatment that helps manage her symptoms & has struggled finding her way in a difficult healthcare system. For now, her life revolves around her health, dogs, family, and friends as she continues on the search to finding the right treatment and getting her life back! She is honored to share with you her tricks on how to navigate a complicated health care system & her stories about some of the tough moments she has faced.  Be sure to subscribe to the Peer Med Podcast on Apple Podcasts, Spotify, Overcast, or wherever you get your podcasts! Follow the Peer Med Podcast on Instagram @peermedpodcast for more patient stories, disease and inspiring eye-opening content! Follow Samantha on Instagram: @sammiegee11 and visit her website: www.myundiagnosedjourney.com 

Translation
What boosts immune boosters? with Kevin Litchfield

Translation

Play Episode Listen Later Sep 16, 2021 49:06


Episode Summary: Novel drugs that boost the immune system to fight cancer have become pharma darlings in the few short years since their approval. These drugs, known as immunotherapies, have so far focused on improving T cell responses and can be used to cure a multitude of different cancer types. Yet more often than not, immunotherapies have no effect on a patient, leaving doctors guessing on whether to prescribe the drug. To find the reason why some people respond while others don't, Kevin and his team create a huge database of sequences derived from immunotherapy-treated patients. With it, he discovers biomarkers, mutational signatures, and immune profiles that correlate to response with the hopes that one day, these measurements form a diagnostic to ensure we treat the right patients.Episode Notes:About the AuthorKevin is a group leader at University College London and performed this work in the lab of Charles Swanton at the Francis Crick Institute. Dr. Swanton and his group are experts in studying the genome instability and evolution of cancer.Kevin started his career as a mathematician but was always driven to apply his skills to improving medicine.Key TakeawaysImmunotherapies aim to cure cancer by “taking the breaks off” your immune system, supercharging it to attack tumors.Two immunotherapies known as checkpoint inhibitors (CPI), anti-CTLA-4 and anti-PD-1, work by enhancing T cells and have recently become blockbuster drugs for the treatment of multiple different cancer types.These immunotherapies don't work in many patients and medicine has yet to understand why.Kevin aggregated DNA and RNA sequencing data across multiple studies to generate a dataset that contained over 1,000 CPI treated patients who did and did not benefit from treatment.With this data, Kevin discovers mutational signatures, biomarkers, and immune profiles that correlate to whether a patient will respond to treatment.TranslationKevin finds measurable signatures of a patient's cancer that could be used to determine whether a patient should receive CPIs.This retrospective analysis will need to be validated as a prospective study to determine whether Kevin's findings actually predict response.More tumor data as well as information about the patient's genetics is being brought in to improve the accuracy of this prediction.Collaborations between academics, medical centers, non-profits, and industry partners will enable the findings to make an impact on patient outcomes.First Author: Kevin LitchfieldPaper: Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Digital Pathology Podcast
Immuno-oncology 101 w/ Elfirede Nößner, HelmholzZentrum, Visiopharm advisor

Digital Pathology Podcast

Play Episode Listen Later Sep 6, 2021 34:47 Transcription Available


This episode is brought to you by VisiopharmCancer immunotherapy, aka immuno-oncology, is tapping into the power of our own immune system to fight cancer. There are multiple processes and immune cell populations involved in tumor immunology and digital pathology and whole slide imaging has allowed scientists to leverage the power of tissue image analysis to detect and quantify them.Today's podcast guest, Prof. Elfriede Noessner will walk us through the complexities of the immune system, explain how it is being influenced to cure cancer and what role tissue image analysis plays in the process. In the course of her research she studied the following processes relevant for immuno-oncology together with the cells responsible for them:·       Killing: T-cells·       Removing the debris of the tumor: macrophages·       Antigen presentation: dendritic cells·       Antibody production: B-cells·       Immune response regulation: regulatory T cells and checkpoints: CTLA4 and PD1/PDL1Killing is crucial for destroying the tumor, but without removing the debris of the killed cells the surrounding tissue will suffer. Antigen presentation enables the immune system to see the enemy. If we do not have antigen presentation, the T-cells responsible for the killing process are blind.Antibody production is an upcoming research area of immuno-oncology however the processes are not well understood yet. Regulation of the communication – stopping the immune response, prevents overshooting. In the body's fight against the tumor, this regulation is coming too early, it stops the T-cells before killing all the tumor cells. This is detrimental in tumor oncology. The stopping proteins are called checkpoints (e.g., CTLA4, PD1/PDL1) and to keep the T-cell attack going on, they need to be inhibited. Seeing is believing, so visualizing the cells and checkpoints has a great convincing effect for the scientific community, but it is also crucial for evaluating the effectiveness of the immune system. It makes it possible to see if the immune cells are in the right location and in the right number. A great example of this proving that the numbers of T-cells in the tumor influence the patient prognosis more than the classical pathology grading is the Immunoscore® of colon cancer. Quantification with image analysis of the numbers and locations of T-cells in colon cancer patients changed the way colon cancer therapy was approached. This was a breakthrough proving that T-cells can matter. However, they do not work all the time and the task of the scientists is to figure out how to activate them. We need to understand what regulates the T-cells – one aspect is the checkpoints the other part is the regulatory cells. If the regulatory cells are close to the T-killer cells, the killer cells are inhibited. This can be only evaluated in an image – the proximity of the different cell types matters, and image analysis is the only way to accurately determine this information. The immune system is a complex entity, but in order to fight cancer, we need to understand and learn to influence it. Digital pathology and image analysis have become indispensable tools in this mission.  

Cancer.Net Podcasts
2021 Research Round Up: Gynecologic Cancers, Melanoma, and Cancer in Adults 65+

Cancer.Net Podcasts

Play Episode Listen Later Aug 16, 2021 55:38


ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, 3 Cancer.Net Associate Editors discuss new research in cervical cancer, melanoma, and cancer in adults 65 and over, presented at the 2021 ASCO Annual Meeting, held virtually June 4th through 8th. This episode has been adapted from the recording of a live Cancer.Net webinar, held August 9th, and led by Dr. Merry Jennifer Markham, Dr. Ryan Sullivan, and Dr. William Dale. Dr. Markham is Chief of the Division of Hematology and Oncology and a clinical professor in the Department of Medicine at the University of Florida. She is also the Cancer.Net Associate Editor for Gynecologic Cancers.  Dr. Sullivan is board certified in medical oncology and an attending physician in the Division of Hematology/Oncology at Massachusetts General Hospital. He is also the Cancer.Net Associate Editor for Melanoma and Skin Cancer.  Dr. Dale is a clinical professor, the Arthur M. Coppola Family Chair in Supportive Care Medicine, and director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center. He is also the Cancer.Net Associate Editor for Geriatric Oncology.  Full disclosures for Dr. Markham, Dr. Sullivan, and Dr. Dale are available at Cancer.Net. Greg Guthrie: Good afternoon, everyone. I'm Greg Guthrie, and I'm a member of the Cancer.Net content team. And I'll be your host for today's Research Round Up webinar. This webinar will focus on gynecologic cancers, melanoma, and cancer in adults age 65 and older. Cancer.Net is the patient information website of the American Society of Clinical Oncology, also known as ASCO. Our participants will be answering questions at the end of this webinar during the Q&A session. Please note that the participants cannot answer questions about anyone's personal medical situation. If you have specific questions about your cancer care, please contact a member of your health care team. Today we'll be addressing research from the 2021 ASCO Annual Meeting, which was held virtually in June, and our participants are members of the Cancer.Net Editorial Board. Now, they are Dr. Merry Jennifer Markham of the University of Florida Health. Dr. Markham is the Cancer.Net Associate Editor for gynecologic cancers. Dr. Ryan J. Sullivan of Massachusetts General Hospital Cancer Center, Harvard Medical School. Dr. Sullivan is the Cancer.Net Associate Editor for melanoma and skin cancer. Dr. William Dale of City of Hope Comprehensive Cancer Center. Dr. Dale is the Cancer.Net Associate Editor for geriatric oncology. And thank you, everyone, for joining us today. So starting us off today is Dr. Markham with highlights in gynecologic cancers. Dr. Markham: Thank you so much, Greg. It's great to be here talking about a couple of studies that were presented at ASCO. Just to point out that I don't have any conflicts of interest for either of the 2 studies that I'll be presenting today. This first slide is a study that looked at a database to answer a question. And really, the primary question the study was trying to answer was whether HPV screening or cancer screening or HPV vaccination has made any difference in the United States over the last 15 years for HPV-associated cancers. And so the primary population that the results of this study really impact are any people, all people at risk for HPV-associated cancers, and these include oropharyngeal squamous cell carcinoma cancers. So head and neck cancers, anal and rectal squamous cell carcinomas, vulvar, vaginal, and cervical squamous cell carcinomas, and penile as well. So this study evaluated data from 2001 to 2017 in a database, the U.S. Cancer Statistics Database, and specifically tried to answer these questions. And the findings were rather complex, broken down by men and women, and so I'll walk you through. In women, the overall incidence of HPV-related cancers was 13.68 per 100,000. And so of those cases, 52% were cervical cancer. What the authors found is that over the last 16 years, the incidence of cervical cancer decreased at an annual percent change of 1.03%. So a decrease annually by a little over a percent. And the incidence of cervical cancer in 2017 was 7.12 per 100,000. Over that same timeframe, the incidence rates of other HPV-associated cancers in women increased significantly. So rather than decrease, they went in the opposite direction. And specifically oropharyngeal, head and neck cancer, increased by 0.77% annually, anal and rectal cancer increased by 2.75% annually, and vulvar squamous cell carcinoma increased by 1.27% annually. Specifically in women over age 80, the incidence of anal and rectal cancer approached that of cervical cancer. The incidence of cervical cancer in that age population was 6.95 per 100,000, which was a decrease of 2.9% annually. Anal and rectal cancer incidence in women over 80 was 6.36 per 100,000 or 1.23% increase annually. So the authors did a projection model and found that the incidence in women of anal and rectal cancer was expected to surpass that of cervical cancer by the year 2025 for every age group over age 55. Now if we switch to men, the incidence of all HPV-related cancers was 11 per 100,000 in the year 2017 and 81% were head and neck cancers. Over the last 16 years, there was an increase in HPV-related cancers in men 2.36% per year, with the highest increase in head and neck cancers, 2.71%, and in anal and rectal squamous cell carcinomas, 1.71% annual increase. Those who were at highest risk of head and neck cancer, the squamous cell carcinoma that I'm referring to, were older men. They were ages 65 to 69 with an incidence rate of 36.5 per 100,000 and an annual increase of 4.24%. White men actually had the highest incidence. So white men ages 65 to 69 had the highest incidence of head and neck squamous cell carcinoma at 41.6 per 100,000. So it's a lot of numbers, a lot of data. Boiled down, what this really means is that cervical cancer has been decreasing. All other HPV-related cancers have been increasing. Now, the decrease in cervical cancer incidence is likely a combination of factors. Primarily, we have regular screening for cervical cancer, and we have HPV vaccination. Now, the risk for other HPV-related cancers, such as head and neck and anal and rectal squamous cell carcinoma, does remain high and is increasing, unfortunately. These are not cancers with routine screening. And so the authors concluded, and I think this makes sense, that screening and vaccination efforts, specifically HPV vaccination efforts, might help to impact those rising cancer numbers and help to decrease those rising incidence rates. So that is study 1. Greg, are we ready to go to the next one? Greg Guthrie: Yeah, we are. Dr. Markham: So this is the OUTBACK study. This is adjuvant chemotherapy following chemoradiation. That's primary treatment for locally advanced cervical cancer compared to chemoradiation alone. This was a phase III randomized study. We refer to it as the OUTBACK study, which was its official name. And this study sort of hits at the opposite end of that HPV cancer-related spectrum. So we're out of the prevention and in sort of incidence arena now in a realm of treatment. So this study impacts women who had locally advanced cervical cancer and specifically those who were able to be treated for cancer with chemoradiation. And just to clarify, chemoradiation, when that term is used together usually means chemotherapy and radiation given at the same time. And the chemotherapy is usually designed to make the radiation work better. So standard practice, the standard treatment that oncologists give for locally advanced cervical cancer is chemotherapy with a medicine called cisplatin and radiation, and this together is again chemoradiation. So the question the authors wanted to ask in this study was whether adding chemotherapy at the end of chemoradiation helped to improve survival outcomes. So the study compared 2 groups, 1 group of women - and this was randomized - received chemoradiation alone. And that's absolutely standard of care practice. The other group, the experimental group, received chemoradiation, which was standard, but an additional 4 cycles of chemotherapy with a platinum and a taxane chemotherapy agent. The primary endpoint was overall survival. The study took a little bit of time to accrue. It recruited from 2011 to 2017, and ultimately 919 women with locally advanced cervical cancer were eligible and were analyzed in this dataset. Of those, 456 were assigned to chemoradiation, and 463 were assigned to chemoradiation followed by the additional 4 cycles of chemotherapy. What the study found is that overall survival at 5 years was similar in both groups. So 71% for the standard treatment arm and 72% for the arm that received the 4 additional cycles of chemotherapy. In addition, the progression-free survival was similar at the 5-year mark. So 61% compared to 63%. I think important to note is that this is a negative study. So the 4 additional cycles did not make a difference for these women. However, 81% of the women who were assigned to the chemoradiation and the chemotherapy had grade 3 to 5 adverse events within a year of being randomized, compared to only 62% of women who received the chemoradiation alone. So more women who received that experimental arm had more toxicity, more adverse events. As we like to do in any randomized study, the authors did evaluate both groups of women to make sure there were no differences, and there were no statistical differences inherent between those 2 groups, and patterns of their cancer recurrence were similar in both groups. So what does this mean for our patients? For women with locally advanced cervical cancer, what we know now based on this study is that the standard treatment really does remain chemotherapy with radiation concurrent, so given simultaneously, and that we actually don't get any improvement in survival by adding additional chemotherapy. We do get extra side effects and extra toxicity. But women do not have better outcomes with this regimen. And that's it for these 2 studies, Greg. Greg Guthrie: Thanks, Dr. Markham. I was wondering if you could really quickly give a sense of scope for how much do grade 3 through grade 5 adverse events affect somebody's well-being, quality of life. Dr. Markham: Yes, absolutely. So typically, a side effect on a clinical trial are graded from 1 to 5. 5 is the absolute worst. That typically is death from a treatment. Grade 1 is very mild side effects such that you as a patient, if you're being treated with that, that treatment course may not really have much in the way of side effects or symptoms. But once we get to grade 3 and 4, there is some consequence. So, for example, for someone with anemia, they might actually require hospitalization or a blood transfusion. So it's definitely not a mild side effect. These are what we would consider significant or severe. Greg Guthrie: Thanks, Dr. Markham. Now we'll move on to Dr. Sullivan with highlights in melanoma. Dr. Sullivan: Greg, thanks so much for the introduction. It's a pleasure to be here today, and I'd like to thank Cancer.Net for the opportunity to provide highlights in melanoma from the Annual Meeting at ASCO. So I thought what I would do is show a few pictures and then describe what these pictures mean. So, the first study that I'm going to talk about is actually not a new trial. This is probably the fifth or sixth time this trial has been presented at ASCO. It's the CheckMate 067 study, which is a trial. And if you look at the upper right, this is a randomized trial. So patients were randomized to receive in gray ipilimumab, which at the time of this study launch was the standard of care for patients with newly diagnosed, advanced or metastatic melanoma. Patients could have been randomized to nivolumab, which had been shown to be effective in the second line after ipilimumab and was being compared in the front line with ipilimumab. And then the third arm and that-- was sorry, that's in green. And then the third arm in orange is the combination of nivolumab and ipilimumab. As I said, this trial has been presented many times, but this follow-up presentation was with 6 and a half years of following how patients did on the study. And I don't generally like to show survival curves, certainly not overall survival curves, but I want to show them in this scenario, because what we're seeing, if you look at the lower left, this is progression-free survival. These are patients who started therapy and then their disease hasn't-- when the curve sort of flattens out, that means that whatever that number is, that's probably the number of patients at least with 6 and a half years follow-up, who are likely to remain progression-free over time. We know with ipilimumab, which is the gray line, and it shows 7% of patients who started therapy remain without growth of their disease. We know that those patients, if you're alive and without evidence of disease progression at 5 years, you're probably alive and without disease progression at 10 years. And that may be true for the combination of nivolumab and ipilimumab and nivolumab, which are the green and orange lines. And what's important about that is this is probably the potential cure rate of these therapies. As you can see, the numbers at 60 months and the numbers at 78 months don't look a lot different. And I would anticipate that about 30% of patients treated with nivolumab, which is a PD-1 blocking drug, and more than that, maybe 33 or 34% of patients treated with the combination of nivolumab and ipilimumab, are cured of their melanoma, which was metastatic at the time of starting treatment. And that is really amazing, particularly because this is a disease before these drugs came around that generally led to the death of greater than 90% and closer to 95% of patients who developed it. And that leads me to the second curve, which is the lower right, which shows that at 6 and a half years of follow-up, almost half of the patients treated with ipilimumab and nivolumab are alive and again, compared to probably less than 5% in historical dataset. So this is without a doubt, the most remarkable data when thinking about how patients do with melanoma that's ever been shown, and that's why I wanted to show these pictures. This sort of picture shows actually the number of patients who are alive and treatment-free. So one of the important concepts of oncology, and I think if patients are polled, generally speaking, they would like a therapy that works, they would like a therapy that's tolerable. And ideally, if that therapy makes your disease go away, they'd like a therapy they can stop. And so on the left where it says nivo-plus-ipi and “n equals 145,” what it's saying is that 77% of patients who are alive in and were randomized to that regimen are treatment-free, meaning they never needed another therapy. For the nivolumab, that's 69% of the patients. And for ipilimumab, that's 43% of the patients. And so I think the other point that I wanted to make is that not only does this therapy lead to really remarkable outcomes, but it also leads to one of the key metrics that we want, which are control of disease and not needing to be on therapy. So to summarize, this study was patients previously untreated with unresectable stage 3 or stage 4 melanoma. It's a 6 and a half year update. And it's a randomized trial of nearly 1,000 patients. This, again, is the longest follow-up data of any anti-PD-1 therapy, with or without an anti CTLA4 antibody like ipilimumab. A durable progression-free survival was seen in about a third of patients with a combination, about 30% of patients with single agent nivolumab, and less than 10% with single agent ipilimumab. And the durable overall survival is close to 50% with the combination, over 40% with single agent nivolumab, and just over 20% for ipilimumab. And then again, importantly, patients alive at this data cutoff, almost 80% with the combination remained off of therapy and never required subsequent therapy. And then one other important point that was presented by the authors was that in patients who had complete or partial responses, about 80% of those who were treated with a combination, those complete or partial responses were maintained over this time. That was compared to almost 90% of the complete response to the nivolumab, but only a little more than 60% of the partial response with nivolumab were durable. And this is a question that as an oncologist caring for melanoma patients, I'm asked all the time by my patients who have a nice response to therapy, "How long's it going to last, Doc?" And the answer is, in the majority of patients, it seems to last at least 6 and a half years. And again, having additional follow-up data is really important to be able to answer these key questions. So what does this mean for patients? Say the data suggests that a significant minority of patients treated with either the combination of ipilimumab plus nivolumab or single agent nivolumab have durable benefit. I'm not sure if I said it, but it's important that I do say it, that I have been a paid and an unpaid consultant with Bristol Myers Squibb, who is the sponsor of this trial, since 2017. That goes for this presentation as well. So another really critical presentation that was made at ASCO this year was the so-called RELATIVITY-047 study. So this, again, was a randomized trial. This randomized over 700 patients to either the combination of relatlimab plus nivolumab or to nivolumab by itself. Relatlimab is an anti-LAG-3 antibody. Nivolumab is in the anti-PD-1 monoclonal antibody. Anti-PD-1 antibodies have become the standard of care for a number of different cancers, either in combination or by itself. And they block a key way that the cancer's preventing the immune system from attacking it. Relatlimab is another drug in targeting another one of these important molecules that cancers can use to help prevent immune destruction. And so the idea here is that blocking 2 of these key proteins that the cancer cells may be using to help prevent their destruction by the immune system might be better than just blocking 1. So this is the progression-free survival. So, again, the number, the percentage of patients over time whose disease hasn't grown since starting the therapy. And what was shown is that the combination was better than just nivolumab by itself at preventing growth of disease. And to say it another way, of preventing disease progression. And this is busy, and it's not meant to be kind of seen, but essentially that where you see all of those little teal bubbles next to a dotted line, they're all to the left of that dotted line. And that generally means that the combination was better in a lot of different subgroups of patients based on sex, based on age, based on how functional the patients were when they went in, based on BRAF mutation status. And importantly, they look to see whether or not this was true also for patients who had PD-L1 expression, which is an important, potentially predictive factor of nivolumab treatment, as well as LAG-3 expression, which again was the target of one of the drugs. And the hint here is that there seems to be benefit no matter whether the tumor expresses PD-L1 or not, and whether the tumor expresses LAG-3 or not. So to summarize, this is another study looking at patients previously untreated, unresectable stage 3 or 4 melanoma, randomized 700 patients, over 700 patients to either a combination of a LAG-3 inhibitor, relatlimab, and a PD-1 inhibitor and nivolumab versus nivolumab by itself. The trial met its primary endpoint. The combination was well-tolerated, although there was some increased toxicity with the combination compared to the single agent. But it doesn't appear that the toxicity is significantly dose limiting, and the majority of patients were able to continue therapy and similarly to those who were treated with nivolumab. And then this subset analysis, it consistently favored the combination. So what does this mean for patients? Well, the data suggests that the combination of relatlimab and nivolumab may be a new standard of care in patients with advanced melanoma. However, there are caveats, including it's contingent on this combination being approved by regulatory authorities. And also important to note that there's no data yet to determine whether this combination would replace or be better than the combination of the ipilimumab and nivolumab, the combination that I talked about in that first presentation that I'm summarizing as part of the CheckMate 067 study. So we really don't know whether this will be replacing frontline therapy for all patients who have unresectable stage 3 or 4 melanoma or just a subset. But it does seem that this data is potentially revolutionary in terms of how we manage this disease. And finally, I'm going to talk about a clinical trial of a product called lifileucel. This is a trial sponsored by a company called IOVANCE, and I served on a scientific advisory board for the company over a year ago. This is a trial that was looking at the benefit of something called TIL therapy. So TIL stands for tumor infiltrating lymphocytes. So in tumors, we often can identify immune cells that may just be hanging around and watching what's going on or actually may be there with bad intentions, meaning they got there because they can recognize the tumor and are trying to destroy it. And long ago, in the 1990s, a group at the National Cancer Institute began to develop ways of removing these tumor infiltrating lymphocytes, testing whether or not the lymphocytes could recognize a tumor and then would give them back to patients. The cells themselves are unmodified other than they come out, they're grown, expanded, and then given back to patients. The way this works is that a patient will have a tumor removed. So call it the harvest. The lymphocytes or TILs will be removed. They'll be expanded. They'll be tested to see if the TILs actually recognize the cancer. And then a patient will be hospitalized, given chemotherapy to basically prepare their body to receive the TILs. The TILs will be given. And then patients will receive something called interleukin-2, which is a growth factor for the T cells. And then patients remain in the hospital until their blood counts recover from the chemotherapy. And then that's it. That's the only therapy that's given as part of TIL therapy. So this study was looking at cohort 2, which was patients who had previously been treated for melanoma with a PD-1 blocking drug and then received TILs because the PD-1 blocking drug wasn't working and they needed another therapy. In the bottom left is a curve called a waterfall plot. Down is good. The down can go to 100%, which means that all the tumors that were measurable went away. And in the majority of patients' tumors got smaller. And about 35 to 37% of patients actually had what we call partial response or a complete response. And those responses to the right is shown that they tended to be ongoing and that with a median follow-up of over 30 months, the majority of responders remained in response. So 1 concern is do these responses last, and the answer is they seem to. So to summarize, this was a trial for patients who had unresectable stage 3 or stage 4 melanoma who were previously treated with an anti-PD-1 antibody. This was an update of a clinical trial for lifileucel. Sixty-six (66) patients were enrolled. The majority had received both ipilimumab and an anti-PD-1 antibody. This it says upfront toxicity. That's why patients are in the hospital. But once patients leave the hospital, there tends to be very few long-term toxicities. Over 35% of patients had a response, and the majority of those responses were maintained with nearly 3 years of follow-up. One additional thing that was presented is that patients who actually had the poorest prognosis factors going in, meaning their disease grew right away when they got immunotherapy before or they had what's called an elevated LDH, those patients actually seem to have the best responses, the best outcomes. So what does this mean? Well, lifileucel's been shown to be effective in a subset of patients with PD-1 resistant disease, the anti-PD-1 resistant disease. And this data suggests that patients with primary refractory disease, anti-PD-1 may benefit the most. And it remains to be seen whether or not this becomes a standard therapy. But if it does, this data supports its use in this setting. I'll stop there. Thanks, Greg. Greg Guthrie: All right. Thank you, Dr. Sullivan. And now we'll turn to Dr. Dale, who's going to discuss highlights in geriatric oncology research. Dr. Dale: Well, thank you so much, Greg. And thanks to my fellow panelists, to ASCO, and Cancer.Net for the chance to present this exciting new work in cancer and aging or cancer with older adults. I'm going to present 3 studies, 2 of which are related to each other in that they're both about cognitive loss with the treatment of cancers, and a second one about the pre-existing deficits, which also partners with the others. So I think a really nice, natural follow-up to my colleagues who talked about the risks of balancing toxicities and treatment effects, which is often highlighted for older adults. So the first study by Schiaffino, et al. is identifying pre-existing dementia in older adults diagnosed with cancer through a national claims database. I'll mention up front that I am a mentor for Dr. Schiaffino, but not of this particular work, which was done independently with another group of providers and mentors. So this study was done in older adults with cancer who were found to have pre-existing dementia of the Alzheimer's type or a related kind of dementia. So the advance of this case is to take a large database, not a clinical trial database, and through the development of a unique algorithm, actually, 2 of them, identify people who have perhaps unknown pre-existing dementia or cognitive impairment. These are all patients over 65 years old in Medicare, combined with a national cancer database called SEER, which is Surveillance, Epidemiology, and End Results study, for about a 10-year period. And it was conducted in people with 6 different kinds of common cancers. And what did we find that was new in this study? It's surprisingly common using this algorithm adapted from clinical diagnostics for people to have pre-existing cognitive impairment concerning for Alzheimer's or another dementia. This is often thought to be quite low, probably because most people with cognitive impairment do not end up enrolled in clinical trials. But if you look at a real-world database like this, 15 to 30% were found to have evidence of pre-existing cognitive losses. So they assessed the prevalence of this pre-existing disease through this algorithm across the cancer types, and it was even more common among certain racial and ethnic subgroups, basically non-white subgroups compared to white subgroups. Again, white individuals are more commonly enrolled to significant degrees in clinical trials. So what does this mean for patients and caregivers if up to 1 in 3 older adults facing cancer treatment have pre-existing dementia, evidence of Alzheimer's, or related dementia? They need to be identified and screened for in advance of being treated for their cancer. Why is this important? Patients with cognitive impairment are at an increased risk for both overtreatment and undertreatment for their cancers. Those with pre-existing cognitive loss are at very high risk for a number of different toxicities and at high risk for mortality when being treated with chemotherapy and other kinds of cancer treatments. And if it's not identified in advance, they could be placed at higher risk and may want to reconsider the therapy choices. If someone is identified with dementia or cognitive impairment, one thing they're at especially high risk for, as we'll see in the next study, is chemotherapy-related, additional cognitive impairment during treatment, which can lead to a number of complications such as delirium and other problems. On the flip side, patients with dementia are often, as we saw with trials, not offered the most aggressive therapies, even when they're not at risk and offered the appropriate support. And so they're at risk of being undertreated based on perhaps an early kind of dementia that would be perfectly appropriate to be treated. So caregivers and family members may need to advocate on behalf of their older relatives or parents or grandparents to get appropriate treatment. So it's important to ask your oncologists and your primary care doctors about the risks when deciding what treatments and in some cases to undergo appropriate screening and testing for cognitive impairment prior to starting treatment. So the next study is another study of cognitive impairment moving in the direction that the field of cancer and aging is moving, which is identifying effective interventions rather than simply identifying risk factors. So this is a phase II study of 2 combined interventions, exercise and low-dose ibuprofen for cancer-related cognitive impairment, essentially chemobrain, during chemotherapy for patients with cancer led by Dr. Janelsins and their team at the University of Rochester. Who does this study affect? Patients with cancer receiving chemotherapy who are facing cognitive difficulties with the initiation of chemotherapy and testing for 7 different domains of cognition, including memory, attention, concentration, and executive function, among a few others. This was 86 participants reporting cognitive difficulties during chemotherapy. The majority were breast cancer patients, and the vast majority were women. I do note that patients' average age was 54, younger than our usual cutoff of 65, but highlighting the fact that cognitive difficulties can be identified at any age with chemotherapy. I mentioned the 7 cognitive tests. Patients were then randomized into 3 different groups versus placebo for 6 weeks: an exercise alone arm, which included a walking program and a resistance band training program which has been validated in other contexts for cancer patients; daily ibuprofen, 200 milligrams given twice a day by itself; or a combination of exercise and low-dose ibuprofen together. And what did they find, particularly for the issue of attention? So this is the ability to maintain attention on a cognitive task. Exercise alone was the most valuable intervention. People were able to maintain their attention for a significant amount of time, over 20 seconds. Ibuprofen alone also improved significantly compared to placebo at about 10 or 11 seconds. Interestingly, the 2 together had a non-significant improvement in attention of about 8 seconds and raises some questions about why the 2 together would work less well than either alone, perhaps suggesting they use similar mechanisms. Self-reported cognitive function was also found in both of the exercise groups to be improved. So this was the subjective experience of chemobrain was seen to improve in those randomized to the exercise arms. So what does this mean for patients with cancer receiving chemotherapy? These simple, validated, home-based exercises improved attention and the self-reported or subjective sense of cognitive performance. These are things that could easily be done in the home during chemotherapy and may well improve the situation for those who are experiencing chemobrain. Low-dose ibuprofen, just 200 milligrams, that's 1 over-the-counter pill twice a day, improves the same attention, although not quite as much as exercise. Again, the caveats are noted that these were younger patients. The benefits may be even greater for older patients who are more likely to have cognitive impairment, as we saw, and that it was primarily breast cancer patients and primarily women. There are still questions remaining about why the combination was less effective than either intervention alone. And the last study I want to talk about is about other kinds of pre-existing conditions for older adults, focusing on those not with earlier stage disease, but with poor prognosis patients. So this was patients over 65 with poor prognosis cancers defined as a median survival expectation of less than 1 year and combined 2 large databases. To understand this, the Health and Retirement Survey, a large nationally representative study, combined with claims information or people's experience utilizing the health care system or on Medicare, and identified over 2,000 older adults with cancer, and just assessed the frequency of these pre-existing conditions, all of which are detected with a geriatric assessment, which is our standard way of assessing older patients with cancer and as part of the ASCO guidelines that were published a couple of years ago. 26% of the patients had lung cancer, 14% had GI cancer, and 60% had other kinds of cancers. What was found? Patients with poor prognosis have high rates of these pre-existing geriatric conditions. Of greatest concern, perhaps, is daily activities difficulties with well over 60% having difficulty climbing stairs, which are in the homes of many people, nearly 50% had trouble standing up from a chair, and a quarter had trouble walking 1 block. This is important as we anticipate giving people chemotherapy to know that the functional losses should be accounted for in advance, if at all possible, and to be prepared for people who may have lived in a house with stairs for many years or who have a low-slung chair that's difficult to get out of, that will become even more of a problem in the future. About a third of people over the year had a significant fall, 12% of which resulted in injuries, again, suggesting that changes in the home or a falls assessment be done or physical therapy to strengthen prior to treatments. And as we noted, just the last couple studies with cognitive impairment, nearly 1 in 10 had trouble managing their finances and another 6% had difficulties with their medications, highlighting additional challenges that come with older adults when they start on chemotherapies and helping anticipate problems that could be addressed or adjusted for. Of note, as people get older, these problems become even more pronounced. In those who are 85 and older who had cancer, over half had falls and even more presented cognitive problems with a fully one-fourth difficulty managing money, 12% difficulty taking their medications. Often, they're on a number of additional medications, just highlighting the challenges for simply getting through their days and anticipating that in the decision-making for starting on therapy or providing the appropriate support prior to starting on therapy. So I don't have conflicts of interest with this study or the prior study of any kind. And that's my last slide. Oh, I'm sorry, I have 1 more. Let me do the “what this means for patients and families.”  Advanced cancer is often accompanied by these geriatric conditions that affect health, functional status, cognitive status, falls, and social support is another common one along with the establishing appropriate goals of care. These conditions are detectable with the geriatric assessment. Here I've linked to the ASCO guidelines that came out in 2018. It's now becoming more of a standard of care for older patients. I will point out with the geriatric assessment, it does not require time in clinic to be conducted. It can be done in advance of clinic, and it can be done with nursing support or other staff doing it. Oftentimes online questionnaires can be answered so that these issues can be identified even prior to coming to the clinic or being seen in a video call. Interventions can improve many of these outcomes. We heard earlier from Dr. Markham about chemotherapy toxicities. Geriatric assessment interventions have been shown to decrease toxicities. Polypharmacies, so the reduction in the number of medications that are required that may not be appropriate any longer. Completion of advanced directives goes up with the use of geriatric assessment interventions, and the decision-making choices that need to be made for cancer therapies, whether it's chemotherapy or immunotherapy or others, are enhanced and happen more often with the geriatric assessment being done and help to mitigate the long-term outcomes, especially toxicities and geriatric issues that come up for older adults. I think with my last slide, my timing is just about perfect, Greg, so thanks. Greg Guthrie: It is perfect, Dr. Dale. So thanks very much for that. And now we can move on to our Q&A session. And we can see what questions we have. Ah, so our first question is for Dr. Sullivan, and it is, is relatlimab a checkpoint inhibitor or is LAG-3 not a checkpoint? Dr. Sullivan: Excellent question. LAG-3 is an immune checkpoint. Immune checkpoints are molecules that-- I guess the way to step back is to say that to have an active immune response, there needs to be a few things to happen. Typically what the immune response we're talking about against cancer is T-cell immune response. And so the T-cells need to be able to recognize something like a piece of tumor protein that's expressed on the outside of the tumor, like a flag. And then once they've sort of, there's this teaching process or priming process and then that process is involved. So there's a lot of these so-called checkpoints. Some of these checkpoints actually activate the immune system better, and some of these actually block the immune system from working well. And it's this delicate balance. It's almost like our immune systems have to be in the Goldilocks zone so it's not too hot, not too cold, but just right. And so a lot of these drugs, these checkpoint inhibitors, are blocking drugs to either activate cells or once the cells are activated and get into the immune microenvironment of the tumor, then they have to navigate these other potential checkpoints. And so PD-1 and PD-L1 are checkpoints on the immune system that are targeted by drugs like nivolumab, pembrolizumab, atezolizumab. And another checkpoint is LAG-3. So LAG-3 is expressed on what we call exhausted immune cells or T-cells. And so blocking LAG-3 can actually overcome that exhaustion and make those immune cells work better. So LAG-3 is a checkpoint and relatlimab is a checkpoint inhibitor. And that was a long way of saying it. Greg Guthrie: One of the things that's really interesting about that study is that relatlimab is used in combination, and is that to reach that kind of Goldilocks situation that you were saying? Dr. Sullivan: It's like the Goldilocks zone. Yeah, not too hot, not too cold. Greg Guthrie: Just right. Dr. Sullivan: Well, relatlimab and nivolumab are trying to make the immune system hotter. And so that's a good thing when we're talking about anticancer immunity. The downside, and to Dr. Markham's and Dr. Dale's points about toxicity, the downside of having the immune system too hot is that it can lead to side effects, and those side effects are generally inflammatory. So we worry the more checkpoints we inhibit, that the more side effects we'll see. So the combination in that first study of ipilimumab and nivolumab, when we use that combination, we get a lot of side effects that can be very challenging to get patients through that treatment, which is why we're looking for other combinations that will be more effective than just nivolumab or pembrolizumab by itself, but also will lead to substantial and better antitumor outcomes. Greg Guthrie: Great. All right. We have another question, this one for Dr. Dale. How often do doctors evaluate patients for ADRD, or if they do not, will they still go ahead and provide chemotherapy? Dr. Dale: Always risky for me to say what doctors do. I feel like I'm talking about my oncology colleagues like the anthropologist in Mars, I sometimes say where I'm just the geriatrician observing. So I don't know what people do for sure. We do know is that it's still not common for geriatric assessments that include cognitive screening tests to be done in oncology practices for a number of reasons. Resources is a particular challenge. So we already have very busy oncologists, particularly community oncologists, but all of them. And to fit in a cognitive screening test can be a real challenge. And so we have to come up with a different systematic way. Having said that, do they go ahead and treat? I think in most cases when people with dementia are identified, they are less likely to be treated for the concerns people have for cognition. But the way it's identified through family report in patients is known to be inconsistent and not as good as formal testing. So what I would say is we're getting better at creating screening tests that take very little time to do some cognitive assessment. And those who are screened as positive can then be sent for appropriate follow-up with a geriatrician or to a neurologist, whatever is appropriate. But those who are not can then move ahead with chemotherapy and not be excluded. So we're getting there, but there's more work to be done. Greg Guthrie: Okay, great. And not a follow-up question, but another question for you, Dr. Dale. It seems like we've gotten a couple of questions about ibuprofen. So what is the mechanism by which ibuprofen is thought to improve or affect cognitive function in older adults with cancer? Dr. Dale: Great. And I'm not an expert in the cognitive impairment directly, more in the health services sense, but my understanding is older adults are especially affected by inflammatory responses. So being frail, for example, is associated with inflammatory markers in our system such as CRPE and other inflammatory markers. And it's thought that ibuprofen as an anti-inflammatory reduces that. And those same markers are associated with this chemobrain cognitive impairment in several different studies. These are still association, so we can't say they're causal relationships. But the hypothesis is if we give ibuprofen and lower the inflammatory profile, that will allow cognition to improve and attention by extension. There is another theory I'll put out there. This is my personal one that I'm a little more sympathetic to, which is the inflammatory response from cancer and cancer treatments is fatigue. And fatigue is by far the most common side effect as Dr. Markham can tell us on the toxicity profile. It's very prevalent. For older adults, being fatigued affects cognition just like it does physical functioning. And it's very difficult to concentrate when you're so tired. And to the extent that we can reduce that inflammatory response and reduce the sense of fatigue, the more people could concentrate. Again, none of this is proven. This is still all at the hypothesis testing stage. Greg Guthrie: Great. Our next question is for Dr. Markham. Is there any indication from the research that either vaccine, this HPV vaccine, or screening alone made the difference in the lowered incidence rate for cervical cancer? Or was it a combination of vaccination and screening? Dr. Markham: So I don't think we know the answer to that really, and I have not seen it in studies. We have data that screening is helpful and we have data that the HPV vaccine is helpful.  So I suspect that it's the combination, but I don't know how much of each is contributing. I do think that like many things with cancer, it does take a multiple-pronged approach whether to treat it or to diagnose it. So to me, it makes sense that it's some combination of the 2. Greg Guthrie: So a quick follow-up. For a lot of the squamous cell carcinomas that are included in that HPV study, they conclude by saying that there aren't a lot of screening protocols in place for these types of cancer. Do you think that we have the knowledge to do screening for those cancers and we just don't? Or will further research be needed to find ways to detect and prevent? Dr. Markham: So I think like many of these things, we do need more research. The challenge with screening research is that we have to prove, our scientists have to prove that you can screen a lot of people safely and not in a costly   manner and actually reduce the incidence of cancer or some other outcome. And those studies are actually really hard to do, and they take a long time. I think the data that has come out on prostate cancer screening and on breast cancer screening with mammograms and at what age do we start and so on and so forth, I think is just a testament to how complicated the screening studies can be. So do we have the ability to screen? I think yes. I know that some dentists, for example, and head and neck doctors, head and neck specialists like ENT physicians, are able to just visually take a look in the mouth, for example, to screen for any abnormalities that look like cancer. Do we as a country or a health system have the ability to do that on a large scale [not] in a costly manner? I don't know the answer to that. And that's where we really do need more research. And same with anal and vulvar cancers, etc. Greg Guthrie: That's great. Thanks, Dr. Markham. So I think we're going to move on to our final question, and that's for you, Dr. Sullivan, is how similar is TIL therapy to CAR T-cell therapy? Dr. Sullivan: That's a great question. Both are T cells that are taken from a patient and given back to the same patient. But a CAR T-cell is made by removing a bunch of white blood cells from the blood and then those white blood cells, those T cells, are modified so that they are able to recognize the cancer. And when they do, the immune cell turns it on and they can actually expand. It's really like a living and modifying kind of in real time drug. And so there are a few of those CAR T cells that are approved by the FDA to treat a number of different diseases that express what we call an antigen that the CAR T recognizes. T-I-L therapy, or TIL therapy, are T cells that are removed from the tumor itself. They are not modified in the way, at least, that the standard NIH protocol, which is the protocol that we presented today and was presented at ASCO, which essentially is take the cells from the tumor, expand them, grow them, make sure they recognize the tumor, and then give them back. And so the difference is-- their similarities is they're both T cells and the T cells theoretically can recognize the cancer. The differences are that CAR T cells are taken from the blood and modified, and TILs are taken from tumors and are not modified. Greg Guthrie: Great. That's very clear, Dr. Sullivan. Thank you, and thank you to all of our panelists for joining us today and sharing this great research and, of course, your expertise. It's been a real pleasure. And to all of you who attended this Research Round Up webinar, thank you to all of you for joining us today. You can find more coverage of the research from the ASCO Annual Meeting and other scientific meetings at the Cancer.Net blog. That's Cancer.Net/blog. If you're interested in more Cancer.Net content, please sign up for our monthly Inside Cancer.Net newsletter or follow us on social media. We're on Facebook, Twitter, and YouTube. And our handle is always @CancerDotNet with dot spelled out. Thank you for everybody for attending, and have a good day. Thanks. ASCO: Thank you, Dr. Markham, Dr. Sullivan, and Dr. Dale. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

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TOP ASCO 2021: Melanoma

ScienceLink

Play Episode Listen Later Jun 23, 2021 33:12


El Dr. Jerónimo Rodríguez Cid, oncólogo médico adscrito al Instituto Nacional de Enfermedades Respiratorias en la Ciudad de México, México, junto al Dr. Luis Ubillos, oncólogo médico subdirector del Insituto Nacional del Cáncer INCA-ASSE en Montevideo, Uruguay, nos comentan sobre lo más destacado en melanoma presentado en ASCO 2021, resaltando los siguientes estudios: Melanoma (adyuvancia): KEYNOTE 054: Estudio fase III, aleatorizado, doble ciego el cual evaluó a 1019 pacientes con melanoma. Su objetivo primario fue comparar el tratamiento de inmunoterapia adyuvante con un anticuerpo monoclonal anti-PD-1 (pembrolizumab) vs. placebo después de la resección completa de un melanoma en estadio III de alto riesgo. SWOG 1404: Estudio fase III, doble ciego el cual evaluó a 1378 pacientes con melanoma resecado de alto riesgo y que comparó el tratamiento con interferón de dosis altas o ipilimumab vs. pembrolizumab. Melanoma (metastásico): RELATIVITY 047: Estudio fase II/III, doble ciego, aleatorizado el cuál evaluó a 700 pacientes con melanoma metastásico o irresecable no tratado previamente. Este comparó el tratamiento de relatlimab combinado con nivolumab vs. nivolumab solo. CHECKMATE 064: Estudio fase II, aleatorizado, de etiqueta abierta con 138 pacientes inscritos con melanoma avanzado o metastásico, el cual evaluó el tratamiento de nivolumab administrado secuencialmente con ipilimumab. ABC: Estudio fase II, aleatorizado, de etiqueta abierta el cual evaluó a 76 pacientes con melanoma con metástasis cerebrales y que comparó el tratamiento de nivolumab vs. nivolumab + ipilimumab. COLUMBUS: Estudio fase III multicéntrico, abierto, aleatorizado, el cual comparó dos partes de LGX818 + MEK162 vs. la monoterapia con vemurafenib + LGX818 en 907 pacientes con melanoma BRAF V600 mutado irresecable o metastásico. Pembrolizumab + lenvatinib: Estudio que evaluó la combinación de pembrolizumab + lenvatinib en pacientes con melanoma que hayan progresado a un tratamiento anti-PD-1 o anti-PD-L1 previo. Abstract “Eficacia de la inhibición de los puntos de control en el melanoma acral avanzado”: La población de este estudio consistió en pacientes del Registro Holandés de Tratamiento del Melanoma prospectivo a nivel nacional entre 2014 - 2020, y la tasa de respuesta objetiva fue calculada en todos los pacientes con melanoma acral no resecable en estadio III y IV y con melanoma cutáneo, los cuales fueron tratados con anti-PD1 y con la combinación anti-PD1 + anti-CTLA4.

The Uromigos
Episode 67: The Third Uromigos Debate - PD1/VEGF vs PD1/CTLA4 for front line renal cancer

The Uromigos

Play Episode Listen Later Nov 17, 2020 28:48


David McDermott and Brian Rini debate treatment options in front line renal cancer. It's hard to identify any winners from this podcast.

La Ciencia Pop
S01E37 | El blues del linfocito

La Ciencia Pop

Play Episode Listen Later Nov 13, 2020 32:37


Se supone que el sistema inmune ha evolucionado para protegernos y, sin embargo, parece que es muy poco lo que puede hacer para combatir a las células cancerosas; células que parecen haberse rebelado contra nuestro cuerpo y que el día de hoy causan alguno de los tantos tipos de cáncer, que se han convertido en una de las causas de muerte más importantes. Durante mucho tiempo se pensó que debido a que las células cancerígenas derivan de células normales, era muy poco lo que el sistema inmune  –que en condiciones normales no ataca a nuestro cuerpo– pudiera hacer algo al respecto y tal vez faltaba encontrar un factor que explicara como se relaciona el sistema inmune con los tumores. A pesar de uno que otro destello en la oscuridad, generaciones de investigadores habían intentado encontrar este factor perdido, pero invariablemente fracasaron. Nadie podía ni siquiera decir con certeza que tal factor existía y hoy les voy a contar la historia de ese descubrimiento, que involucra a un texano amante del blues y que toca la armónica *** La Ciencia Pop es auspiciado por Más Audio, donde cuentan con la tecnología más avanzada y los más cómodos y modernos audífonos de origen alemán. Con los mejores precios del mercado, tecnología de punta y un servicio de primer nivel, en Más Audio te pueden ayudar a ti o un familiar a volver a oír los sonidos que ya no escuchas. Para más información, visita la página www.masaudio.cl o escribe al correo quiero@masaudio.cl. También puedes visitar sus páginas en Facebook o su tienda online en tienda.masaudio.cl y mencionando “La Ciencia Pop”, te darán un 5% de descuento en la compra de audífonos. No te lo pierdas ***Support the show (https://www.patreon.com/LaCienciaPop)

The Uromigos
Episode 66: Uromigos Paper of the Month - Two papers in Nature Medicine on neoadjuvant immune combinations in bladder cancer

The Uromigos

Play Episode Listen Later Nov 9, 2020 30:49


Pam Sharma and Michiel Van Der Heijden discuss neoadjuvant PD(L)1 + CTLA4 inhibition in urothelial cancer.

HOPA Now
[Education] Melanoma and Non-Melanoma Skin Cancers: Top 10 Clinical Pearls

HOPA Now

Play Episode Listen Later Jul 6, 2020 12:21


HOPA Now is the official podcast of the Hematology/Oncology/Pharmacy Association, an organization dedicated to supporting pharmacy practitioners and promoting the advancement of Hematology/Oncology/Pharmacy to optimize the care of individuals impacted by cancer.   These educational podcasts are part of our BCOP Preparatory and Recertification Course, which is designed to prepare oncology pharmacists preparing to sit for the BCOP Certification Exam, as well as meet the BPS requirement to complete a BCOP Preparatory/Recertification Review Course.   In this episode of HOPA Now, Dr. Laura Alwan shares ten clinical pearls regarding melanoma skin cancers, including immunotherapy as a main treatment option in melanoma cancers, management of related adverse events, and other patient considerations for immunotherapy. She also highlights specific considerations for select immune-related adverse events, offers timelines for high dosage steroids, and details treatment options for unique melanoma cancers.   In this episode you will learn:   Melanoma skin cancer treatments Immunotherapy as a main treatment option in melanoma cancers The when and how of immune-related adverse events Data and symptoms surrounding PD1 inhibitors and CTLA4 inhibitors, including dose-related toxicities How to monitor and manage immune-related adverse events Specific considerations for select immune-related adverse events, including rapid GI transit Timelines for managing high dose steroids Treatment and management options for patients with BRAF mutations Unique therapy for melanoma through the use of T-VEC   Mentioned in This Episode: HOPA   Quotes:   “Melanoma is known to have a high degree of somatic mutations and has a unique relationship with the immune system.” — Laura Alwan   “It’s important for the oncology pharmacist to consider if infection prophylaxis is warranted.” — Laura Alwan  

MOC Brasil
Podcast #020_ASCO 2020 | Imunoterapia no câncer de pulmão células não pequenas avançado

MOC Brasil

Play Episode Listen Later Jun 14, 2020 12:44


Neste Podcast, Dra. Carolina Kawamura Haddad, oncologista clínica da BP – A Beneficência Portuguesa de São Paulo, comenta três estudos que se destacaram nesta edição da ASCO na área de imunoterapia em câncer de pulmão células não pequenas (CPCNP) avançado. O estudo fase III CheckMate 9LA, que consolidou mais uma opção de tratamento para o CPCNP EGFR/ALK negativo, com a combinação de quimioterapia + nivolumabe + ipilimumabe. O estudo CCTG BR.34, que randomizou 301 pacientes com CPCNP EGFR/ALK negativo para receber a combinação do anti-PDL-1 durvalumabe com o anti-CTLA4 tremelimumabe versus a mesma combinação com quimioterapia. A análise não demonstrou benefício em sobrevida global com a adição de quimioterapia e dupla imunoterapia. O terceiro trabalho comentado (CheckMate 227) teve apresentada a atualização do braço de ipilimumabe e nivolumabe versus quimioterapia isolada também em pacientes com CPCNP EGFR/ALK negativo tanto na população PDL-1 positivo quanto PDL-1 negativo. Os resultados demonstram benefício com a combinação de ipilimumabe e nivolumabe.

PODC’AFUF
9.L' IMMUNOTHERAPIE - Pr YANN NEUZILLET

PODC’AFUF

Play Episode Listen Later Apr 29, 2020 5:17


En 2 mots comment ça marche ? PD1-PDL1, CTLA4… c’est quoi tout ça ?Pourquoi faire de l’immunothérapie précocement ?Comment ça se passe en pratique ?Comment gérer les complications ?Le Professeur Yann Neuzillet (Hôpital Foch - Suresnes) répond à toutes vos questions !L’orateur n’a pas reçu de rémunération pour la réalisation de cet épisode.Pour aller plus loin :Pourquoi l'urologue doit s'intéresser à l'immunothérapie, quelles sont les indications établies en 2018 et celles en perspectives ? https://doi.org/10.1016/j.fpurol.2018.05.005Avec le soutien du laboratoire JANSSENMusique du générique : Via AudioNetworkResponsable projets AFUF : Dr Benjamin PradèreProduction : La Toile Sur Ecoute See acast.com/privacy for privacy and opt-out information.

Neurology Minute
CTLA4 Deficiency

Neurology Minute

Play Episode Listen Later Jan 23, 2020 2:18


Dr. Stacey Clardy talks about CTLA4 deficiency and relevance to neurology.

Journal of Clinical Oncology (JCO) Podcast
Advancing Treatment Options for Mismatch Repair-Deficient Metastatic Colorectal Cancers

Journal of Clinical Oncology (JCO) Podcast

Play Episode Listen Later Jan 8, 2020 8:05


This podcast reviews the results of KEYNOTE 164 investigating the use of pembrolizumab for mismatch repair deficient metastatic colorectal cancer, the place of this agent in the current clinical paradigm, and future directions to identify which patients are most likely to benefit from this treatment strategy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'A Phase II, Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164' by Le et al. My name is Dustin Deming, and I am an associate professor at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin. My oncologic specialty is gastrointestinal oncology. Microsatellite instability high status or mismatch repair deficiency is found in approximately 15% of early stage colorectal cancers, but only 3-4% of metastatic colorectal cancer. The mechanisms by which these cancers acquire their DNA repair aberrations can vary, including germline mutations, somatic mutations and promoter methylation, which is often observed in the setting of the hypermethylation phenotype associated with BRAF mutations. This distinct colorectal cancer subtype is of particular interest for immunotherapy strategies as the lack of adequate mismatch repair can lead to 1000s of mutations and also fusions leading to the potential for expression of more neoantigens.   This world-wide phase 2, open-label study enrolled 124 patients with microsatellite instability high or metastatic mismatch repair deficient colorectal cancer following 2 or more lines of standard therapy in cohort A and following 1 or more lines of therapy in cohort B. Patients received pembrolizumab 200 mg every 3 weeks, up to 2 years, until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review and secondary endpoints included duration of response progression-free survival, overall survival, safety and tolerability.   At the time of this report the median follow-up for cohort A was 31.3 months and 24.2 months for cohort B. The objective response rate was 33% for both cohorts. This includes 7 patients who achieved a complete response. The median PFS was 2.3 months for cohort A and 4.1 months for cohort B. For those patients that developed an objective response the duration of response was quite prolonged with the median duration of response not reached in either cohort. The median overall survival was 31.4 months for cohort A and not reached in cohort B. This treatment was well-tolerated in this population with the most common toxicities being fatigue, pancreatitis, and increased alanine aminotransferase or lipase.   Overall pembrolizumab is an exciting addition to the treatment strategy for patients with metastatic mismatch repair deficient cancers. Based on these results, in part, this agent is now FDA approved for patients with previously treated microsatellite instability high or mismatch repair deficient metastatic colon cancers after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients also for non-colorectal solid tumors following at least one prior therapy, regardless of tumor type or origin. This was the first FDA approval of a tumor histology agnostic anticancer therapy.   Long-term follow-up from this, and similar cohorts, is required to further define the duration of response for these patients, as there is hope that some of these patients could even be cured. Unfortunately, it is only a minority of patients that seem to benefit from this approach as demonstrated by the short median progression free survival in both cohorts. A better understanding of which patients are likely to benefit from immunotherapy approaches are clearly needed.    The presence of Lynch syndrome was not captured in this study to evaluate for differential response in this setting. The BRAF mutation status was collected and across both cohorts 14 patients had BRAF mutant cancers. The response rate for these patients was 43%. A similar benefit was also observed in KRAS or NRAS mutant and wild-type cancers. This study was limited in its ability to further assess those factors that could influence pembrolizumab response given the relatively small sample size and limited biospecimen collection.   Further clinical trials are investigating the use of anti-PD1 therapies for these patients in the first-line and adjuvant settings, in combination with chemotherapy and with other immune checkpoint agents, such as CTLA4 and LAG3, among others. This includes Checkmate 142, which is a phase II study that is examining nivolumab and ipilimumab in a cohort of 46 patients with microsatellite instability high or mismatch repair deficient colorectal cancer in the first-line setting. Preliminary results were presented at the 2018 European Society of Medical Oncology meeting demonstrating a 60% objective response rate and a 12 month progression free survival of 77%. These early results are promising, but further investigation is needed.   As we look forward to which factors could be leading to a lack of clinical benefit from these agents it is important to consider those factors that are intrinsic to the cancer cells, tumor microenvironment, and patient specific factors. Tumor cell intrinsic factors include important cell attributes for the immune response such as the tumor mutation burden, MHC class I expression, including beta-2-microglobulin expression, the mutation profile, including alterations in WNT signaling shown to be important for immunotherapy resistance in metastatic melanoma, and tumor heterogeneity. There is also a growing understanding of factors that are important within the tumor microenvironment for tumors to be permissive to immune cell infiltration. These factors include differences in the immune and fibroblast cell subtypes present and also the presence of certain matrix proteins. This includes a matrix proteoglycan called versican that my laboratory and others have demonstrated has immunosuppressive properties, but can be cleaved by ADAMTS proteases to an immunostimulatory fragment. Additionally, patient specific factors need to be considered such as the microbiome, immunosuppression and adverse event management.   In summary, the results of KEYNOTE 164 are a significant advance for patients with microsatellite instability-high and mismatch repair deficient cancers. Long-term follow-up from this study and further studies into the most efficacious clinical setting to use these agents will continue to advance the clinical use of immunotherapy options for these patients.   This concludes this JCO Podcast. Thank you for listening.

Journal of Clinical Oncology (JCO) Podcast
Resuming Life After Cancer Therapy: Treatment-Free Survival

Journal of Clinical Oncology (JCO) Podcast

Play Episode Listen Later Dec 10, 2019 8:09


Treatment-free survival is a novel endpoint in immunotherapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma” by Regan et al. My name is Adil Daud, and I am Professor of Medicine and Dermatology and Director of the Melanoma Program at the University of California, San Francisco. My oncologic specialty is medical oncology. Cancer therapy has achieved great success in the last 40-50 years. Where treatment with chemotherapy required inpatient hospitalization and gut-wrenching toxicity, therapy today can often be achieved with lower grade side effects and limited time in the hospital or outpatient infusion center. While these changes have brought enormous benefit to patients, many patients feel that the tug of ongoing therapy for metastatic or advanced cancer and long for a time where therapy is not continuing, and the word “cure” is not completely out of mind. Allied to these concerns is the rise and expansion of immunotherapy for cancer. The growth and spread of neoplasm often triggers the immune system, which mobilizes in response. While cancers can use a variety of adaptive mechanisms to evade the immune system, blocking these evasive mechanisms can produce lasting responses and, in some cases, durable tumor-free intervals. Cytokine therapy as exemplified by IL-2 offered this benefit since its approval in the 1990’s for renal cell cancer and for melanoma for approximately 10-20% of patients treated. The CTLA4 antibody, ipilimumab has had a similar long-term disease control rate with a better toxicity profile. However, it is the anti-PD-1 monoclonal antibodies, used by themselves or with ipilimumab that have made treatment-free survival a tangible and achievable goal for many patients with cancer especially those with cutaneous melanoma. Measuring the effect of treatment is traditionally done with measures of disease control. These include tumor shrinkage as measured by an agreed upon method such as RECIST or irRECIST or by lengthening of time-either lifespan or time without progressive disease (progression-free survival). However, it is possible that a similar lifespan could be achieved in one of 2 different ways-either continuous treatment with a drug or a shorter-term treatment that stops within a few months and then the patient has no further treatment. Comparing these treatments that are profoundly different for a patient but similar in terms of standard time or disease control measures demands new measures that can help describe the benefit of one or the other treatment. In the JCO article that accompanies this podcast, Regan et al, in an analysis of 1077 patients across 2 different randomized trials, attempt to provide such a measure. They define treatment-free survival as interval between time to ICI cessation to the time to subsequent therapy or death.  With this measure, the shorter the therapy and the more delayed the need for subsequent therapy (or death) the longer this interval is. Combination immunotherapy is notoriously toxic and while treatment duration can be short, the side effect duration can be prolonged. Could TFS be contaminated with toxicity ? to answer this question, Regan et al introduce another endpoint, TFS with and without toxicity and partition this with persistent and late onset grade ≥3 toxicity. These endpoints are illustrated in Figure 1. Below the familiar Kaplan-Meier overall survival curve is a slice showing survival after subsequent therapy initiation (so factoring in progression). Below this is the TFS without toxicity. Below this slice is the TFS with toxicity and below this is the time on IO therapy. With this division, the familiar KM curve gives a lot more information and illustrates the difference between nivo-ipi combination therapy and nivolumab monotherapy. While the overall survival is not statistically different between these 2 treatments (as shown in previous publications) the TFS lets us see what is going on with patients. In Figure 4 we can see that in the combination nivo-ipi arm the TFS (mean) is 11.1 months vs 4.6 months for nivo alone and 8.7 months for ipi alone. These numbers indicate that TFS alone does not convey the full picture as ipi beats nivo in this measure due to the short duration of ipi treatment while extensive previous data including from keynote 006 show us that pd-1 therapy exceeds ctla4 therapy in virtually every other measure of health. If we look at TFS subtracting toxicity, again ipi nivo beats nivo handily with 10 months vs 4 months but again ipi with 8.5 months slots in the middle. Figures 5A, 5 B and 5C show us the TFS partitioned by grade ≥3 treatment-related adverse events, grade ≥2 TRAEs or by the use of  immune suppressants. To summarize this interesting manuscript, overall survival can be subdivided into TFS and time on therapy and time following subsequent therapy. The TFS can be further subdivided into TFS with or without toxicity (≥2 or ≥3 TRAE or use of immune suppressants). These additional  measures give some granularity to the survival and let us see what exactly survival constitutes, time off treatment and toxicity or time on treatment and with side effects. These measures have several limitations: one of the important ones is introducing differences between treatment arms which by primary outcome measures have no difference by standard PFS or OS and by favoring short duration high toxicity treatments (such as ipi) over low toxicity, low intensity chronic treatments (such as nivo). These are value judgements which matter to many patients but need to be understood as such. In oncology, we need to make these value judgements explicit and make the tradeoffs clear. Ultimately though, the importance of TFS and similar outcome measures may be that they encourage this conversation and help our field open up to what matters. This concludes this JCO Podcast. Thank you for listening.

Blood & Cancer
Choosing a melanoma therapy with Dr. Justine Cohen

Blood & Cancer

Play Episode Listen Later Oct 17, 2019 30:26


Justine V. Cohen, DO, of the University of Pennsylvania, Philadelphia, joins Blood & Cancer host David H. Henry, MD, also of the University of Pennsylvania, to discuss a recent melanoma case in the adjuvant setting and when to consider targeted therapies or immune checkpoint inhibitors for these patients.  Plus, in Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, talks about what happens when a patient’s anxiety threatens to get in the way of the clinician’s decision making. Time stamps: Meet the guest (00:51) This Week in Oncology (03:02) Interview with Dr. Justine Cohen (05:48) Clinical Correlation (26:25) This week in Oncology FDA approves rivaroxaban for VTE prevention in hospitalized, acutely ill patients by Lucas Franki FDA approval for the new indication is based on results from the phase 3 MAGELLAN and MARINER trials, which included more than 20,000 hospitalized, acutely ill patients. Therapies for melanoma Classes of therapies for adjuvant melanoma include immune checkpoint inhibitors and targeted therapies. Historically, high-dose interferon was the only available therapy for melanoma. This was associated with a lot of toxicities, without great benefits in terms of overall survival. About 50% of melanomas are BRAF mutated and amendable to adjuvant treatment with the combination of BRAF/MEK inhibitors. Immunotherapy can be used in BRAF mutated patients or BRAF wild type (no mutation). Ipilimumab (anti-CTLA4) demonstrated recurrence-free survival benefit and an overall survival benefit. Toxicity = grade 3 or grade 4 immune-related side effects. Nivolumab and pembrolizumab (anti-PD1) have taken the place of ipilimumab. They are associated with lower rates of toxicities (14%-15%). Side effects of immunotherapy: “itis” (fever, ocular toxicity, lung, colon, rash, many others). These side effects may persist despite cessation of immunotherapy unlike targeted therapies, in which side effects resolve after stopping. Treatment decisions following adverse events depend on how much therapy is delivered prior to the event and the severity of toxicity.   Drug Class Mechanism of action Interferon Antiviral ·   Inhibits protein synthesis ·   Inactivates viral RNA ·   Enhances phagocytic and  cytotoxic mechanisms   Ipilimumab Checkpoint inhibitor ·   IgG1 monoclonal antibody against cytotoxic T-lymphocyte antigen 4   Nivolumab Checkpoint inhibitor ·   Human IgG4 monoclonal antibody against programmed death 1 (PD-1)   Pembrolizumab Checkpoint inhibitor ·   Human IgG4 monoclonal antibody against programmed death 1 (PD-1) Dabrafenib Targeted therapy ·   BRAF inhibitor   Vemurafenib Targeted therapy ·   BRAF inhibitor Trametinib Targeted therapy ·   MEK inhibitor    Show notes by Emily Bryer, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia. References Weber J et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824-35. Eggermont AMM et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789-1801. Long GV et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813-23.   For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc Ilana Yurkiewicz on Twitter: @ilanayurkiewicz  

Medicine Matters oncology
Understanding the relationship between the gut microbiome and immunotherapy (with Jennifer Wargo)

Medicine Matters oncology

Play Episode Listen Later Jun 24, 2019 13:28


Recent research has shown an association between intestinal microbiota and response to immunotherapy in the setting of various tumor types. Listen to Jennifer Wargo, from The University of Texas MD Anderson Cancer Center in Houston, USA, share her insights into the findings. Find more on Medicine Matters oncology This content was originally published on Medicine Matters oncology (https://oncology.medicinematters.com/) on January 28, 2019.

Immune
Immune 14: Braking bad

Immune

Play Episode Listen Later Nov 14, 2018 80:17


The Immune team explains the science behind the 2018 Nobel Prizes awarded to Allison and Honjo: checkpoint immunotherapy. Hosts: Vincent Racaniello, Stephanie Langel, and Cynthia Leifer Subscribe (free): iTunes, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode 2018 Nobel Prize in Medicine 2018 Nobel Prize in Medicine (pdf) What's in a name?(Can Res Inst) Checkpoint inhibitor failures(Nature) Image credit Time stamps by Jolene. Thanks! Weekly Science Picks Steph- Immunobites Cindy- List of immunology Nobels Vincent- Prof. Barker's Immunology lectures Music by Steve Neal. Immune logo image by Blausen Medical. Send your immunology questions and comments to immune@microbe.tv

This Week in Virology
TWiV 514: Staying below the ADAR

This Week in Virology

Play Episode Listen Later Oct 7, 2018 108:29


The TWiVumvirate reviews this years crop of Nobel Prizes, and how cells prevent leakage of mitochondrial double-stranded RNA into the cytoplasm, which would otherwise lead to the production of interferon. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, and Kathy Spindler Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode Sea Phages program and application materials Plant biologists penalized by CNRS (The Scientist) 2018 Nobel Prize in Medicine (pdf) 2018 Nobel Prize in Chemistry (pdf) 2018 Nobel Prize in Physics (pdf) 2018 Nobel Peace Prize (Nobel) Mitochondrial dsRNA triggers IFN (Nature) Letters read on TWiV 514 Timestamps by Jolene. Thanks! Weekly Science Picks 1:28:33 Alan- Compound Interest chemistry graphics Kathy- Writing letters of recommendation Guidelines Trix & Psenka Schmader et al. Madera et al. Dickson- Japan Fireworks Vincent - The Game of T-Cells and Apple Park Lego Listener Picks Steve - Shomu's Biology Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Immune
Immune 4: Putting the immunotherapy CAR T before the cancer

Immune

Play Episode Listen Later Jan 23, 2018 83:15


The immu-knowledge-ists deconstruct the holy grail of oncologists, cancer immunotherapy, and the exciting development of CAR T cells and how they work. Hosts: Vincent Racaniello, Stephanie Langel, and Cynthia Leifer Become a patron of Immune! Links for this episode Synthetic Immunoreceptors for Cancer Therapy (Trend Mol Med) Engineering immune cells to treat cancer (Cell) Engineering T cells for fungal infections (PNAS) CAR T cells for AIDS (PLoS Path) CAR T cells (NIH) Image credit Letters read on Immune #4 Weekly Science Picks Cindy - What's In A Name? Steph - Novel Targets Vincent - Friendly Penguin Music by Steve Neal. Immune logo image by Blausen Medical. Send your immunology questions and comments to immune@microbe.tv

ESMO Open
New therapeutic targets in the inflammatory microenvironment

ESMO Open

Play Episode Listen Later Sep 5, 2017 7:59


In this podcast, Editor Anna Berghoff speaks to Professor Eric Tartour (Department of Immunology; Hôpital Européen Georges Pompidou) about new therapeutic targets in the inflammatory microenvironment. The introduction of immune checkpoint inhibitors introduced a new era of oncology. The CTLA4 or PD1/PDL1 axis targeting immune checkpoint inhibitors have shown remarkable and long lasting responses in a variety of tumor types, Here, the biology of immune checkpoint inhibitors is outlined including the main site of action for the different immune checkpoint inhibitor types. Further, other possible immune checkpoints like LAG3 and other cells types including macrophages and NK cells as future directions for immune modulating therapies are discussed. Combination approaches including immune checkpoint inhibitors and chemotherapy or radiotherapy are currently investigated for their synergistic efficacy and preliminary data has shown promising results. Read the Abstract on the ESMO Open website: http://esmoopen.bmj.com/content/3/1/e000310.

EADO 2017
PD1/ CTLA4 : Upfront or sequentially?

EADO 2017

Play Episode Listen Later Aug 1, 2017 9:02


Prof Hoeller speaks with ecancer at EADO 2017 about the timing of combination therapies using PD-1 and CTLA-4 targeted therapies to treat melanoma. While these targets have been subject to a great deal of investigation independently, Prof Hoeller notes that there is no trial assessing the two in a direct comparison for upfront combination, or one after the other. He considers the patient subgroups which may benefit most from these differing approaches, based on tumour infiltration and LDH levels, and weighs how toxicity may be managed. Prof Hoeller also considers how best to assess patient responses to targeted therapies, based on expression of molecular markers including circulating tumour DNA.

EADO 2017
Update in anti-CTLA4 and anti-PD1 treatment in advanced melanoma

EADO 2017

Play Episode Listen Later Aug 1, 2017 3:20


Dr Blank speaks with ecancer at EADO 2017 about targeting immune checkpoints in melanoma patients with anti-PD1 and anti-CTLA-4 drugs. Dr Blank describes how immune therapy is better suited to certain patient subtypes, and that combined checkpoint therapy may result in significant response or needless toxicity if applied without understanding the biology of the patient and cancer being treated.

2017 ASCO Annual Meeting
Treating advanced melanoma with ipilimumab and HF10

2017 ASCO Annual Meeting

Play Episode Listen Later Jul 28, 2017 5:41


Prof Andtbacka speaks with ecancer at ASCO 2017 about results from a phase II multicenter trial combining intralesionally injected HF10, an oncolytic Herpes virus, with anti-CTLA4 targeted therapy to treat metastatic or unresectable melanoma He describes the encouraging response rates from the small trial group, with 41% overall response at 24 weeks, significantly more than trials using ipilimumab alone, with many patients experiencing a durable response. Prof Andtbacka notes pending analysis of patients responses to assess if age and immune senescence may influence these outcomes, and highlights further trials testing HF10 alongside other immune agents, including a similar trial ongoing in Japan.

This Week in Parasitism
TWiP 135: Embryonated eggs of wisdom

This Week in Parasitism

Play Episode Listen Later Jun 20, 2017 113:33


Dickson returns to the TWiP hosts to solve the case of the Woman from Colorado With Loose Stools, and explain how single-sex infection with female Schistosoma mansoni reduces hepatic fibrosis. Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin Become a patron of TWiP. Links for this episode: ASM Grant Writing Online Course Single-sex Schistosoma infection (PLoS NTD) Asterix the Gaul Letters read on TWiP 135 This episode is brought to you by Blue Apron. Blue Apron is the #1 fresh ingredient and recipe delivery service in the country. See what’s on the menu this week and get your first 3 meals free with your first purchase – WITH FREE SHIPPING – by going to blueapron.com/twip. Case Study for TWiP 135 Patient seen in clinic by Daniel's colleague, living in Queens, needs home care. Man with wound on foot, needed daily care. Living 9 months, recently developed painful blister, he put his foot in water, got great relief, blister opened up. Open lesion did not look normal, there was something in blister. Went to see parasitologist, saw something there, wrapped it around piece of wood. Not previously seen a physician, no surgeries, knew little family history. New to our country, where could he have possibly come from? Rural part of some country. Resource limited region. How many days of treatment will he need? Send your case diagnosis, questions and comments to twip@microbe.tv Music by Ronald Jenkees

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Immunotherapy Combinations

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Play Episode Listen Later Apr 27, 2016 4:35


Dr. Jack West, Swedish Cancer Institute, discusses current trials seeking to determine the efficacy of combining immunotherapy agents in lung cancer.

GRACEcast Lung Cancer Video
Immunotherapy Combinations

GRACEcast Lung Cancer Video

Play Episode Listen Later Apr 27, 2016 4:35


Dr. Jack West, Swedish Cancer Institute, discusses current trials seeking to determine the efficacy of combining immunotherapy agents in lung cancer.

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Immunotherapy Combinations

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Play Episode Listen Later Apr 27, 2016 4:35


Dr. Jack West, Swedish Cancer Institute, discusses current trials seeking to determine the efficacy of combining immunotherapy agents in lung cancer.

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Novel Immunotherapies and Combinations

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Play Episode Listen Later Jan 20, 2016 25:34


Dr. Mario Sznol, Yale School of Medicine, provides a detailed description of the mechanism of action of immunotherapy agents and discusses early data on the use of combination therapies.

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Novel Immunotherapies and Combinations

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Play Episode Listen Later Jan 20, 2016 25:34


Dr. Mario Sznol, Yale School of Medicine, provides a detailed description of the mechanism of action of immunotherapy agents and discusses early data on the use of combination therapies.

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Novel Immunotherapies and Combinations

GRACEcast Treatments and Support Video

Play Episode Listen Later Jan 20, 2016 25:34


Dr. Mario Sznol, Yale School of Medicine, provides a detailed description of the mechanism of action of immunotherapy agents and discusses early data on the use of combination therapies.

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Immunotherapy Combinations: Is this the Future for Treating Lung Cancer?

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Play Episode Listen Later Dec 7, 2015 4:09


As we learn more about immunotherapy for lung cancer, combinations with multiple immunotherapy agents are being explored. Medical oncologist Dr. Eddie Garon considers whether combinations are likely to emerge as the leading immunotherapy approach.

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Immunotherapy Combinations: Is this the Future for Treating Lung Cancer?

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Play Episode Listen Later Dec 7, 2015 4:09


As we learn more about immunotherapy for lung cancer, combinations with multiple immunotherapy agents are being explored. Medical oncologist Dr. Eddie Garon considers whether combinations are likely to emerge as the leading immunotherapy approach.

GRACEcast Lung Cancer Video
Immunotherapy Combinations: Is this the Future for Treating Lung Cancer?

GRACEcast Lung Cancer Video

Play Episode Listen Later Dec 7, 2015 4:09


As we learn more about immunotherapy for lung cancer, combinations with multiple immunotherapy agents are being explored. Medical oncologist Dr. Eddie Garon considers whether combinations are likely to emerge as the leading immunotherapy approach.

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Is It Feasible and Clearly Beneficial to Combine Immunotherapy Approaches?

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Play Episode Listen Later Nov 13, 2015 3:01


Drs. Leora Horn, Ben Solomon, & Jack West review the potential rationale and possible limitations of combining different immuntherapy strategies with one another.

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Is It Feasible and Clearly Beneficial to Combine Immunotherapy Approaches?

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Play Episode Listen Later Nov 13, 2015 3:01


Drs. Leora Horn, Ben Solomon, & Jack West review the potential rationale and possible limitations of combining different immuntherapy strategies with one another.

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Immunotherapy for Kidney Cancer Patients in the Front-line Setting: Coming Soon?

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Play Episode Listen Later Aug 31, 2015 1:58


Current clinical trials are examining the possibility of giving kidney cancer (also called renal cell carcinoma, or RCC) patients immunotherapy as their first option of care upon diagnosis.

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Immunotherapy for Kidney Cancer Patients in the Front-line Setting: Coming Soon?

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Play Episode Listen Later Aug 31, 2015 1:58


Current clinical trials are examining the possibility of giving kidney cancer (also called renal cell carcinoma, or RCC) patients immunotherapy as their first option of care upon diagnosis.

GRACEcast Kidney Cancer Video
Immunotherapy for Kidney Cancer Patients in the Front-line Setting: Coming Soon?

GRACEcast Kidney Cancer Video

Play Episode Listen Later Aug 31, 2015 1:58


Current clinical trials are examining the possibility of giving kidney cancer (also called renal cell carcinoma, or RCC) patients immunotherapy as their first option of care upon diagnosis.

GRACEcast Treatments and Support Video
Redefining Success and Failure in Cancer Immunotherapy Trials

GRACEcast Treatments and Support Video

Play Episode Listen Later Apr 15, 2015 14:42


Immunotherapy Forum Video #30: Immunotherapy for cancer has rewritten the rules for what we consider a successful response to treatment. Some tumors grow before they regress. Dr. Jedd Wolchok discusses why a new measurement criteria was developed.

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Redefining Success and Failure in Cancer Immunotherapy Trials

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Play Episode Listen Later Apr 15, 2015 14:42


Immunotherapy Forum Video #30: Immunotherapy for cancer has rewritten the rules for what we consider a successful response to treatment. Some tumors grow before they regress. Dr. Jedd Wolchok discusses why a new measurement criteria was developed.

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Redefining Success and Failure in Cancer Immunotherapy Trials

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Play Episode Listen Later Apr 15, 2015 14:42


Immunotherapy Forum Video #30: Immunotherapy for cancer has rewritten the rules for what we consider a successful response to treatment. Some tumors grow before they regress. Dr. Jedd Wolchok discusses why a new measurement criteria was developed.

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Immunotherapy for Lung Cancer: Currently Enrolling Clinical Trials of Combination Therapies

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Play Episode Listen Later Mar 30, 2015 11:36


Immunotherapy Forum Video #25: In Part 2 of 2 videos, Dr. Matthew Hellmann discusses currently enrolling clinical trials for lung cancer patients that study combination therapies (meaning an immunotherapy drug plus another drug is given).

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Immunotherapy for Lung Cancer: Currently Enrolling Clinical Trials of Combination Therapies

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Play Episode Listen Later Mar 30, 2015 11:36


Immunotherapy Forum Video #25: In Part 2 of 2 videos, Dr. Matthew Hellmann discusses currently enrolling clinical trials for lung cancer patients that study combination therapies (meaning an immunotherapy drug plus another drug is given).

GRACEcast Lung Cancer Video
Immunotherapy for Lung Cancer: Currently Enrolling Clinical Trials of Combination Therapies

GRACEcast Lung Cancer Video

Play Episode Listen Later Mar 30, 2015 11:36


Immunotherapy Forum Video #25: In Part 2 of 2 videos, Dr. Matthew Hellmann discusses currently enrolling clinical trials for lung cancer patients that study combination therapies (meaning an immunotherapy drug plus another drug is given).

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Kidney Cancer Immunotherapy: CTLA-4 & Vaccine Clinical Trials

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Play Episode Listen Later Mar 11, 2015 11:02


Immunotherapy Forum Video #20: Dr. Lauren Harshman talks about clinical trials studying the CTLA-4 pathway, as well as vaccines. 

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Kidney Cancer Immunotherapy: CTLA-4 & Vaccine Clinical Trials

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Play Episode Listen Later Mar 11, 2015 11:02


Immunotherapy Forum Video #20: Dr. Lauren Harshman talks about clinical trials studying the CTLA-4 pathway, as well as vaccines. 

GRACEcast Kidney Cancer Video
Kidney Cancer Immunotherapy: CTLA-4 & Vaccine Clinical Trials

GRACEcast Kidney Cancer Video

Play Episode Listen Later Mar 11, 2015 11:02


Immunotherapy Forum Video #20: Dr. Lauren Harshman talks about clinical trials studying the CTLA-4 pathway, as well as vaccines. 

GRACEcast Treatments and Support Video
Questions & Answers with Drs. Topalian and Wolchok about Immunotherapy for Melanoma

GRACEcast Treatments and Support Video

Play Episode Listen Later Feb 11, 2015 16:15


Immunotherapy Forum Video #18: Drs. Topalian and Wolchok sat for a moderated Q&A with Dr. Louise Perkins from the Melanoma Research Alliance following their presentations on immunotherapy for melanoma.

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Questions & Answers with Drs. Topalian and Wolchok about Immunotherapy for Melanoma

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Play Episode Listen Later Feb 11, 2015 16:15


Immunotherapy Forum Video #18: Drs. Topalian and Wolchok sat for a moderated Q&A with Dr. Louise Perkins from the Melanoma Research Alliance following their presentations on immunotherapy for melanoma.

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Questions & Answers with Drs. Topalian and Wolchok about Immunotherapy for Melanoma

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Play Episode Listen Later Feb 11, 2015 16:15


Immunotherapy Forum Video #18: Drs. Topalian and Wolchok sat for a moderated Q&A with Dr. Louise Perkins from the Melanoma Research Alliance following their presentations on immunotherapy for melanoma.

GRACEcast Treatments and Support Video
Melanoma Immunotherapy, Pt. 2: The End of the Beginning

GRACEcast Treatments and Support Video

Play Episode Listen Later Feb 9, 2015 11:34


Immunotherapy Forum Video #17: In Part 2 of 2 videos on this topic, Dr. Jedd Wolchok discusses side effects related to immunotherapy, combination therapies, and information about new immunotherapies currently being studied for treating melanoma.

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Melanoma Immunotherapy, Pt. 2: The End of the Beginning

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Play Episode Listen Later Feb 9, 2015 11:34


Immunotherapy Forum Video #17: In Part 2 of 2 videos on this topic, Dr. Jedd Wolchok discusses side effects related to immunotherapy, combination therapies, and information about new immunotherapies currently being studied for treating melanoma.

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Melanoma Immunotherapy, Pt. 2: The End of the Beginning

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Play Episode Listen Later Feb 9, 2015 11:34


Immunotherapy Forum Video #17: In Part 2 of 2 videos on this topic, Dr. Jedd Wolchok discusses side effects related to immunotherapy, combination therapies, and information about new immunotherapies currently being studied for treating melanoma.

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Melanoma Immunotherapy, Pt. 1: The End of the Beginning

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Play Episode Listen Later Feb 4, 2015 11:24


Immunotherapy Forum Video #16: In Part 1 of 2 videos on this topic, Dr. Jedd Wolchok provides a history of one of the first immunotherapy drugs, Yervoy (ipilumumab), and the evidence that led to its approval.

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Melanoma Immunotherapy, Pt. 1: The End of the Beginning

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Play Episode Listen Later Feb 4, 2015 11:24


Immunotherapy Forum Video #16: In Part 1 of 2 videos on this topic, Dr. Jedd Wolchok provides a history of one of the first immunotherapy drugs, Yervoy (ipilumumab), and the evidence that led to its approval.

GRACEcast Treatments and Support Video
Melanoma Immunotherapy, Pt. 1: The End of the Beginning

GRACEcast Treatments and Support Video

Play Episode Listen Later Feb 4, 2015 11:24


Immunotherapy Forum Video #16: In Part 1 of 2 videos on this topic, Dr. Jedd Wolchok provides a history of one of the first immunotherapy drugs, Yervoy (ipilumumab), and the evidence that led to its approval.

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How Do the Different Immune Checkpoint Inhibitors in Lung Cancer Compare?

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Play Episode Listen Later Apr 17, 2014 2:50


Dr. Edward Garon warns that it is still too early to compare which immune therapies will be more effective in treating lung cancer.February 2014.

GRACEcast Lung Cancer Video
How Do the Different Immune Checkpoint Inhibitors in Lung Cancer Compare?

GRACEcast Lung Cancer Video

Play Episode Listen Later Apr 17, 2014 2:50


Dr. Edward Garon warns that it is still too early to compare which immune therapies will be more effective in treating lung cancer.February 2014.

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How Do the Different Immune Checkpoint Inhibitors in Lung Cancer Compare?

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Play Episode Listen Later Apr 17, 2014 2:50


Dr. Edward Garon warns that it is still too early to compare which immune therapies will be more effective in treating lung cancer.February 2014.

1st Immunotherapy of Cancer Conference (ITOC 1)
Dendritic cell vaccination combined with CTLA4 blockade

1st Immunotherapy of Cancer Conference (ITOC 1)

Play Episode Listen Later Apr 3, 2014 3:08


Dr Kris Thielemans (Medical School of the VUB, Brussels, Belgium) talks to ecancertv the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich. Electroporation of dendritic cells (DC) with mRNA allows the loading of these cells with tumour antigens and the functional modification of a cellular vaccine. To this goal, the team provided three different molecular adjuvants to immature, monocyte derived DCs through electroporation with mRNA coding for CD40L, CD70 and caTLR4 or so-called TriMix mRNA. At Vrije Universiteit, Brussels​, clinical trials in pretreated advanced melanoma patients are being performed. These patients are treated with TriMixDC-MEL, a mixture of TriMix-DC co-electroporated with mRNA encoding a fusion of DC-LAMP and 4 different melanoma associated antigens (gp100, tyrosinase, MAGE-C2 or MAGE-A3). In a pilot clinical trial, 24x106 TriMixDC-MEL cells were administrated solely by the intradermal (ID) route. Subsequently, a phase IB was conducted to investigate the safety of administrating TriMixDC-MEL by the intravenous (IV) and ID-route. ID administration of TriMixDC-MEL was found to be feasible, safe, effectively stimulating CD8 T-cell responses, but did not result in objective tumour responses. In contrast, the combined ID/IV administration is associated with distinct but manageable side-effects and has seemingly superior clinical activity as compared to DC administered solely ID in patients with pretreated advanced melanoma. The team investigated the safety and activity of TriMixDC-MEL combined with ipilimumab. This phase II study of TriMixDC-MEL ID/IV in combination with ipilimumab demonstrates anti-melanoma activity in over 50% of the patients with therapy resistant advanced melanoma.

1st Immunotherapy of Cancer Conference (ITOC 1)
Biomarker development for ipilimumab and prostate GVAX treatment

1st Immunotherapy of Cancer Conference (ITOC 1)

Play Episode Listen Later Apr 3, 2014 4:31


Prof Tanja D. de Gruijl (VU University Medical Centre, Amsterdam, The Netherlands) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about personalising the use of immunotherapeutic approaches by using predictive biomarkers, to avoid unnecessary treatment. Immunotherapeutic approaches such as vaccination or immune checkpoint blockade have proven to be clinically active in prostate cancer, but only in certain patients. Prof de Gruijl's team has focused on the clinical efficacy in patients with castration-resistant prostate cancer of the combination of an allogeneic cell line-based vaccine (Prostate GVAX) and an anti-CTLA4 checkpoint inhibitor (ipilimumab) in a Phase-I/II dose escalation/expansion trial. Based on their results they developed an an immune profile to predict clinical outcome. Importantly, cluster analysis revealed pre-treatment expression of CTLA-4 by circulating CD4 T cells and an immune-stimulatory myeloid profile to be dominant predictors for overall survival after Prostate GVAX/ ipilimumab therapy. These flowcytometry-based parameters may thus provide potentially useful and easy-to-use biomarkers for patient selection.

GRACEcast Lung Cancer Video
Immunotherapy for Lung Cancer: Q and A Session (video)

GRACEcast Lung Cancer Video

Play Episode Listen Later Jul 16, 2012 13:40


Drs. Ramaswamy Govindan from Washington University and Julie Brahmer from Johns Hopkins University answer questions about the current evidence and emerging research on immune-based treatments for lung cancer.

GRACEcast Lung Cancer Audio
Immunotherapy for Lung Cancer: Q and A Session (audio)

GRACEcast Lung Cancer Audio

Play Episode Listen Later Jul 16, 2012 13:39


Drs. Ramaswamy Govindan from Washington University and Julie Brahmer from Johns Hopkins University answer questions about the current evidence and emerging research on immune-based treatments for lung cancer.

GRACEcast Lung Cancer Video
Immunotherapy for Lung Cancer: Yervoy, anti-PD-1, Reolysin, & Talactoferrin by Dr. J. Brahmer (video)

GRACEcast Lung Cancer Video

Play Episode Listen Later Jun 14, 2012 23:37


Dr. Julie Brahmer reviews science and early trial results for immunotherapies for lung cancer ranging from cancer vaccines to anti-cancer viruses.

GRACEcast Lung Cancer Audio
Immunotherapy for Lung Cancer: Yervoy, anti-PD-1, Reolysin, & Talactoferrin by Dr. J. Brahmer (audio)

GRACEcast Lung Cancer Audio

Play Episode Listen Later Jun 14, 2012 23:36


Dr. Julie Brahmer reviews science and early trial results for immunotherapies for lung cancer ranging from cancer vaccines to anti-cancer viruses.

Medizin - Open Access LMU - Teil 14/22
Neonatal immune responses to TLR2 stimulation: Influence of maternal atopy on Foxp3 and IL-10 expression

Medizin - Open Access LMU - Teil 14/22

Play Episode Listen Later Jan 1, 2006


Background: Maternal atopic background and stimulation of the adaptive immune system with allergen interact in the development of allergic disease. Stimulation of the innate immune system through microbial exposure, such as activation of the innate Toll-like- receptor 2 (TLR2), may reduce the development of allergy in childhood. However, little is known about the immunological effects of microbial stimulation on early immune responses and in association with maternal atopy. Methods: We analyzed immune responses of cord blood mononuclear cells ( CBMC) from 50 healthy neonates ( 31 non-atopic and 19 atopic mothers). Cells were stimulated with the TLR2 agonist peptidoglycan (Ppg) or the allergen house dust mite Dermatophagoides farinae (Derf1), and results compared to unstimulated cells. We analyzed lymphocyte proliferation and cytokine secretion of CBMC. In addition, we assessed gene expression associated with T regulatory cells including the transcription factor Foxp3, the glucocorticoid-induced TNF receptor ( GITR), and the cytotoxic lymphocyte antigen 4 (CTLA4). Lymphocyte proliferation was measured by H-3-Thymidine uptake, cytokine concentrations determined by ELISA, mRNA expression of T cell markers by real-time RT-PCR. Results: Ppg stimulation induced primarily IL-10 cytokine production, in addition to IFN-gamma, IL-13 and TNF-alpha secretion. GITR was increased following Ppg stimulation ( p = 0.07). Ppg- induced IL-10 production and induction of Foxp3 were higher in CBMC without, than with maternal atopy ( p = 0.04, p = 0.049). IL-10 production was highly correlated with increased expression of Foxp3 ( r = 0.53, p = 0.001), GITR ( r = 0.47, p = 0.004) and CTLA4 ( r = 0.49, p = 0.003), independent of maternal atopy. Conclusion: TLR2 stimulation with Ppg induces IL-10 and genes associated with T regulatory cells, influenced by maternal atopy. Increased IL-10 and Foxp3 induction in CBMC of non-atopic compared to atopic mothers, may indicate an increased capacity to respond to microbial stimuli.