Podcasts about igg1

America Out Loud PULSE with Malcolm Out Loud – My question is about gain of function research. Why is it still being done in America, and why hasn't anyone stopped this research from continuing? Is the damage caused by the covid vaccines irreversible? Has every vaccinated person destroyed their immune system because of the vaccine shifting the human body from producing just IgG1 and IgG3 to 20% IgG4 and is there anything that can be done to reverse it?

America Out Loud PULSE with Malcolm Out Loud – My question is about gain of function research. Why is it still being done in America, and why hasn't anyone stopped this research from continuing? Is the damage caused by the covid vaccines irreversible? Has every vaccinated person destroyed their immune system because of the vaccine shifting the human body from producing just IgG1 and IgG3 to 20% IgG4 and is there anything that can be done to reverse it?

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Research is piling up to reveal that the mRNA vaccines increasingly weaken the immune system with each booster. Jefferey dives deeper into what “HighWire” guests Bret Weinstein, PhD and William Makis, MD both detail – multiple vaccinations causing a class switch in antibody production to an overproduction of IgG4, the antibody responsible for dampening immune response, and underproduction of IgG1 and IgG3, the antibodies responsible for cancer surveillance.

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

Show Notes and Transcript Professor Dalgleish has spoken out about his concerns of the mRNA jab for years. And for the last 2 he has written about the rise of cancers he believes are linked to the jab.  We start by looking back at Professor Dalgleish's career and ask why he chose to speak up and what was the response from his colleagues?  He then delves into this rise of turbo cancers and why he had to sound the alarm despite the struggle to get full transparency from the authorities and "Move on, nothing to see here" is the reply to most requests for data.  His fellow cancer specialists agree with his concerns, but the authorities simply will not listen. Angus Dalgleish is an expert in immunology and Professor of Oncology at St George's Hospital Medical School, London. Article in The Conservative Woman: https://www.conservativewoman.co.uk/massive-cancer-deaths-study-vindicates-my-warnings-over-covid-boosters/ Japan Data: https://www.cureus.com/articles/196275-increased-age-adjusted-cancer-mortality-after-the-third-mrna-lipid-nanoparticle-vaccine-dose-during-the-covid-19-pandemic-in-japan#!/ The Death of Science:      https://amzn.eu/d/2w1wxk4 Interview recorded 15.4.24 Connect with Hearts of Oak... WEBSITE            heartsofoak.org/ PODCASTS        heartsofoak.podbean.com/ SOCIAL MEDIA  heartsofoak.org/connect/ SHOP                  heartsofoak.org/shop/ TRANSCRIPT (Hearts Of Oak) I'm delighted to have Professor Angus Dalgleish with us today. Professor, thank you so much for your time. (Prof Angus Dalgleish) You're welcome. Great to have you. And of course, people will have read, I'm sure, many of your articles, more recently in The Conservative Woman, back before that, I think in certainly The Daily Telegraph and Daily Mail. And since 1991, I know you've been the Professor of Oncology at St. George's University, London. And during this time, you focused on the immunology of cancer and conducted numerous clinical trials involving a variety of vaccines and immune therapy. I know you're well known for your contributions on HIV AIDS research. And of course, you stood for UKIP, which is another part of your story back in 2015. There's so many areas, Professor, I want to talk to you, but maybe you have got a background in understanding vaccines. We'll get on to, I think, the first article you wrote, certainly I read, was back two years ago, actually, on the madness of vaccinating children against COVID, and they started discussing cancer and what you were seeing back in December 2022. I certainly saw it in the Conservative Woman but maybe I can ask you just for a little bit of your background and then we can get on to what you have seen with your patients and the data. Okay well with regards to my background I mean it's, I've been reminded of something I'd forgotten and that is that I'm probably one of the only people in the country who's been an NHS consultant in virology, immunology, general medicine, and oncology. So when I had my chair in oncology, I had a great background in immunology and virology, which is what led me to go into tumour immunology. And I continued working on HIV pathogenesis for several years and worked with colleagues in Norway with designing a very good HIV vaccine, which is the only one that works. But I was staggered that nobody was interested or would support it. And yet the big medical industrial complex, such as the NIH and Big Pharma, kept plowing ahead with vaccines that had the whole envelope in different technologies, and none of them worked. In fact, it was worse than working. They had to stop all these worldwide trials costing billions because the vaccine was worse than the placebo, now so that's a very good entrée as to where I came from with the COVID virus. When that became a pandemic and the sequence became available. I was called up by my colleagues in Norway saying, would I be happy to do the same process? I help identify the major immunological components and avoid all the unnecessary ones, which is the most important thing. And I said yes, obviously. And we started to plan a MAPA plan when they came back and said, this is not an actual virus, this has been released from the lab in Wuhan or escaped then as we put it and the reasons for this was absolutely plain, is that there were charged inserts around the receptor binding site not one or two but six as well as the fusion site, fusion domain and I looked at that you know, and I had a background because I've done so much work on the HIV receptor, even as a clinician I was you know, had a scientific understanding of interactions and what is required etc and it occurred to me that these inserts some of them had been previously published and, you know, by the Wuhan group, they'd said, aren't we clever? We put this insert in and we made this virus more infectious to human cells. This is very good. They went on with two or three. But here we had one with six inserts. Now, my molecular biology, virology friends all told me, oh, don't get excited. All these things happen at random. And here I then realized what a problem was with science, people are only in their boxes, they don't get out of the boxes. Changes in sequence only matter when they translate into the amino acids which translate into proteins and that's what does the interaction, once the amino acids were translated by these inserts they broke all the rules of the game, they were far too too positively charged, which meant that the virus had been altered so it would act like a fridge magnet. So it would zap onto human cells over and above its natural ACE receptor. And when I realized this, it was 100% I was convinced it could not have come from anywhere else because it had broken the rules of biology. And the rules of biology would have edited out those changes because, put it in a simple way, the charge was around pH 8. The charge of any normal virus is around 6 or less. So it was just a supernatural leap. And that's what convinced me. But the big problem was that having written papers in Nature Science, Lancet on HIV and its receptor and how it causes disease and the epidemiology and got them all in the leading papers. When I pointed this out with my colleagues, Nature, Science, all these papers, Lancet, they all turned us down and said, this data is not in the public interest. Seriously, I've got the copies. It is unbelievable. So I realized then that a discussion about the science was being banned. This led to me, and I'm flagrantly admit that, you know, this ended up in us writing a book called The Death of Science, which is actually available, and I've probably got it somewhere. But this was unbelievable that we suddenly realized everything was being censored. I was told by my own university we were not allowed to discuss or research the origin of the virus. Well, I mean, that was really quite draconian. But then where do so many universities get their funding from these days? They're far too reliant on China. So it clearly comes from that source, the way China stopped the WHA doing their work. Now, I'm just going to mention, this is relevant to what you've asked me to talk about, because when we had that spike protein, we realized it was very fully charged. We also looked at it for a homology with now an epitopes. And 80% of it was similar to the human epitopes, some of them unbelievably identical, platelet factor IV myelin. So we said, do not use this as a vaccine, because it will cause all sorts of terrible side effects. This is how you do it. We've learned from HIV, a vaccine is not how much you can put in it, but how little you can put in it. So you go for the Achilles heels of the structure. So if those structures no longer exist, the virus doesn't exist in any variant. So we actually had a blueprint. And we told everybody about this. We had access to the cabinet, the SAGE, Chief Medical Officer of Science. Who basically deemed it all interesting but not relevant. Can you believe that? But they had a point that there was 150 groups reviewed by a Nature paper, all of them so stupid, I use the word advisedly, that they all said, this is our vaccine. They all used the whole spike protein. Well, it was obvious that you must not use the whole spike protein, in the same way we'd spent 30 years saying don't use the whole HIV envelope. And they still haven't got the process. I mean, it is unbelievable stupidity group thing. And anyhow, so we knew there was going to be a big problem if they use the spike protein with autoimmunity, etc. However, that had nothing to do with my interest with cancer at all. What got my interest in cancer in this was when they brought out the booster program. Now, I've done lots of model work on vaccines, you know, basic research funded by charity, done for industry too. And a basic adage is, if a vaccine needs a booster, it doesn't work. So here we are being forced by the government and all the authorities to have a booster when it was all based on the grounds that people who monitor the effects of people who've been vaccinated, their antibody titer falls off. Well, of course it does. I mean, that's what you want. And that was the basis for doing boosters, to stop it falling off. Well, I knew enough then about the booster is that by the time they were talking about rolling out the booster, we were already in Omicron territory. They were boosting a virus that didn't exist on the grounds that there was crossover. And there was all these species, the booster will give you extra protection from crossover. Well, apart from the fact that we'd widely published and it had been downloaded over a quarter of a million times, our objection to using the spike protein and what you should use for a vaccine, with another group of colleagues, I wrote a review of a virus. Coxsackie viruses and the attempts to vaccinate against them and why they had all failed. And actually, the need for them is greater in animal work than it is in humans. But they all fail because the vaccines against coronavirus lead to antigenic sin or immunological imprinting. Once you are vaccinated against a component of that and you challenge with a different variant, it will only see the first component. And it will not see the variants. But it will make antibodies that will bind to them. And then that enhances infection and this explains why people have just woken up scratched their heads and say why does everybody who gets a booster get infected again with COVID in fact three and a half times more likely according to the big Cleveland study and more than twice as likely according to one published after the second vaccine in BMJ, so this was not a surprise. I couldn't believe why nobody heeded and listened to these warnings. And the people that made the decision. It must have made them in ignorance because they certainly didn't read any of this stuff. Otherwise, they'd have been much more cautious. Now, instead, they were being pushed by Big Pharma, who selected the data. It's now obvious that Pfizer, if they had revealed the data, the VAERS data, nobody in their right mind would ever have approved it. And you've had Clare Craig and Norman Fenton on board. So all I can just point out was I was unaware of this carry on at the time, but they brilliantly pointed out that they did it all on relative risk as opposed to absolute risk and the number needed to vaccinate to prevent. If that data had been presented properly, nobody in their right mind would have approved a vaccine. It's just meaningless to have to vaccinate 120 people to prevent one infection. And when the VAERS data came out, it was clear that if you had a serious adverse event, you had a 3% chance of dying. Whereas if you got COVID, you had less than 1% chance of dying. In fact, a lot, lot less than 1% at the very most. So there was no way anybody should have done it. So I would argue that the Pfizer, and I'm not alone in having said that they went into shenanigans and all sorts of smoke and mirror to hide the truth and get everything approved. But, you know, others, such as the state of Texas, are actually suing them for fraud. So, I mean, it's not exactly, it's an open secret. So get back to the booster and the cap.... Could I just ask you just one little sidestep, I remember reading your numerous articles, I think it's probably in the Daily Mail and I remember thinking Professor Angus is saying, speaking his concerns in a great way to stay within certain restrictions and yet get the message out. And I was reading, thinking, this is exactly what I am hearing as a lay person. And you're explaining from your medical professional background. And those articles in the mainstream media, the newspapers, I think were vital in helping people understand what was happening. And you wrote them in such an intelligent, smart way. Well, thank you very much. With regards to the Daily Mail and the articles, I was staggered by the letter. Sometimes they would print a page of letters in the printed edition, and they were all from people saying, thank you so much for helping us understand just what the hell has been going on. You know that was the great thing, the big problem I had with the Daily Mail as soon as I pointed out that there was a problem with the vaccine, I would get to the draft I'd submit it, it'd be accepted and then it wouldn't appear and it had been censored by the chief editor, as soon as it was a vaccine, we now know why, it's because the mainstream media were paid a fortune to push the narrative by the government. A fortune so big that none of them were prepared to challenge it. The Mail did a fantastic job, and I helped as much as I could on the grounds that the lockdowns were madness, and there's no scientific justification for it. It was absolute madness, even to think of a second one. And many others, Carl Heneghan, et cetera, came up, and I was saying that natural immunity, and I was one of the few clinicians to sign the Great Barrington Declaration because that's what I said we should have done straight from day one. In fact, now in retrospect, my gut feeling we didn't need a vaccine program has been proven to be absolutely true because had we done the vitamin D properly and had one or two other drugs out there, we would not, and I include there, without beating around the bush ivermectin, I think Peter Curry's book is absolutely damning how Fauci and others went out of their way to damp that down. And the only reason they did was because you cannot introduce a vaccine if you've got an effective therapy. I mean, I really do believe it was that bad that they were doing this. And so many people suffered. I think it was criminal. I make no bones about that. But the media wouldn't touch my concerns about the vaccine, which is why I ended up publishing them in the Daily Skeptic and the Conservative Women, who, I must say, they challenge anything that they find they cannot collaborate. Corroborate they they check they do their own referencing and everything so they are very very hot and quite a lot of stuff I've had toned down because of challenges to the refereeing for instance etc, but the stuff that they do put out there they're all very happy about it, now what I did and why you were talking is that when the booster came in, I've said it's a complete waste of time. Not only will it induce antibodies to a virus that doesn't exist, but they will lead to more infection. What I wasn't prepared for was that my patients who I was monitoring carefully, who'd been stable melanoma for years, I had half a dozen of them go down within six to eight weeks of the booster program being wheeled out. And they had relapsed. And some of these had been stable for over 15 years. The average was five to seven. And I knew then something was going on because melanoma patients, once they're induced to be stable with immunotherapy like they all had, because I was using immunotherapy 20, 25 years ago, long before it became popular, I knew there had to be a tremendous immune suppression event going on, life event. It's usually bereavement, severe depression, divorce, bankruptcy. Something that goes over three months to cause this. Yet I was seeing it clear. I reported it. I was told by my own people to shut up and stop frightening the patients. There is no evidence. Get the evidence. So I said, you know, I am a canary in a mine and a man with a red flag. It's up to everybody else to react to this. Now, I was told no. I've subsequently seen a dozen and I've continued to shout. And I saw eight cases within my social and family circle of people who developed leukaemia lymphoma after the booster and so we started to say how is it doing that? When it became evident there was a very good, I mean my own group have done work on this, but to me what really convinced it when other people found that t-cell responses were suppressed after the booster not the first and second but after the booster and the t-cell suppression was so bad they called it exhaustion in cancer patients, well we know that the people who've got cancer under good control, it is t-cells nothing to do with antibodies. So the booster was doing more harm than good, it's suppressing the t-cell response, and then I found papers that was even worse on the grounds that the booster switched the IgG1, immunoglobulin class structure antibodies, from ones that would normally be intent on fighting viruses to one that were tolerizing them, tolerizing the IgG. The sort you induce in transplant patients. So not only had you switched the T cell response off, but you'd sent all the antibodies on to be tolerizing so they didn't reject the transplant. Of course the transplant in this case is the cancer so there's no doubt that it popped up, that was a major reason why it popped up, now why it's important to discuss this now is, having been told to shut up and be quiet, I did get by the way, people from all over the world saying thank you for pointing this out, we've seen exactly the same thing. I mean from America, Canada, South America, Europe, South Africa, Australia, all around the world people said we're seeing exactly the same thing. Well now we have this paper that's come from Japan, it's pure statistical analysis of events over COVID, including all causes of death and this is important, not incidents death, and they noticed there was no increase in death of any cause or cancer during the first one and two waves of COVID. But it started in late 21 and continued to rise, hardly doubling in 22. And so the all-cause in 21 went from a few percentage, three or four, to over 9% in 22. Death from cancer went from 1.1 to 2.2 + in 22 these are small figures but it's a very strong trend because it was in all the cancers, it wasn't just in any one and I got particularly interested because there was no great increase in colorectal cancer, which is what we've seen in the UK in fact the colorectal surgeons were the first to phone me and say we're seeing unbelievable colon cancer in young people, and they've all had the booster vaccine. You know, we think there is something related. So I reacted that there was no signal in Japan. And then remember, they have an incredibly different diet. It's a completely anti-inflammatory diet. So they haven't been primed for colon cancer to take off. But all the ones that were killing them were those that killed them before, but much quicker. But I mentioned mortality. I predicted there would be a massive increase in cancer problems just on lockdown alone because we weren't screening. People weren't coming to with their symptoms. We weren't doing the scanning. We weren't getting them on treatment early. So that alone, I predicted more people would die of that lockdown on cancer than would die from any benefit of lockdown on COVID deaths, which we now know there were zero. I mean I think most people will now agree with that, it was introduced far too late on both occasions, it was introduced just as the hot, the waves were dying out, completely utterly pointless, so I was very aware and actually preached a bit that you know, the problem with this issue is cancer incidence is massive, cancer deaths not nearly as much because we've got very good at treating it and the incidence to death can take several years, so here in Japan you've actually got the death rate clearly rising, it's all very statistical this, in one year two year now, That was finished in 2023, submitted in 2023. If we had the 23 data, I would bet that that would be a doubling again, probably, on the 22 data, because they have shown in the data they've got, it's worse with each booster, not just the first. If you have a fourth and a fifth, it gets worse. And what is great about this paper is it goes into explaining how it's actually induced the cancer early as opposed to just waiting for it to develop which is what I would have expected had it just been suppression of the immune system and one thing they have suggested, which I totally go along with and I hadn't thought of it first-hand myself but I'm fully aware and support it, is that the clotting tendency, these micro-clots that the spike protein causes. Actually would lead to enhancing the cancers to spread and metastasize. And we know that this clotting abnormality occurs in some cancers, prostate and pancreas, and all sorts of unusual things occur, like disseminated intravascular coagulation, etc. Now, this is the sort of thing, that it was being reported in people who died of cancer who'd been vaccinated. Really abnormal clots. If you look at the literature, there's a lot of people pointing out that the autopsy is highly unusual clotting going on. So the fact that that process was actually driving cancer is a very interesting suggestion. It's not proof, but it's yet another reason that might be driving it. In the literature are reports that the spike protein binds to p53 and msh3. These are suppressor genes. If you have mutations in these genes you're much more likely to develop cancer because they normally switch the cancer that has arisen by accident off. They're suppressor genes, they switch it off. So if you compromise your suppressor genes you're much more likely to develop cancer quickly. And I think that this is part of what the Japanese data is showing. I just point out that I don't think there is any ulterior motive in just pointing out what we've seen, whereas I am very concerned that the Office of National Statistics keep changing the rules with data. They stopped reporting the COVID deaths in May 22, and they've been doing adjustments and all sorts of things, which I think, what are they trying to hide? And Carl Heneghan has made a very, and Norman Fenton, made a very big issue of this. Why don't they just release all the data? And I'm convinced that data shows something very similar, just because of what I see. I look around my friends, the number who've gone down with cancer since they had the booster. Which they only had so they could travel in lockdown, and they wanted to have a decent holiday. And he said, you can't get on this plane or this boat unless you have the booster. And so they had the booster. And in two cases, they never, ever going to get on the boat and do the traveling. One of them died very quickly, and I was horrified by it because he'd had perfect treatment, absolute perfect treatment, but still progressed, suggesting there were other mechanisms going on. And another one had a lymphoma that he had years ago it resurfaced rapidly and killed him and his oncologist, I was quite surprised told him, I really can't ignore the fact that this has been stable for years but it's come back as soon as you had the booster and there's a chap in England who's pointing this out, I was a friend of this guy, he's in America. And then I've had other cases which have popped up completely unexpected. In my family, I've had cases of leukaemia uncovered after the boosters and brother-in-laws, etc. So it's really real. And friends who developed aggressive prostate, pancreatic, ovarian cancer since the booster program has been wheeled out. And my main reason for shouting about this is that I am still being told I can have a spring booster to protect myself. I spoke to a friend today and they were talking about their father who was told he had prostate cancer and I think he went for a psa testing, that's to look at how far the cancer is and it was very low it was six or eight, then after the boosters he went for another test and they'd gone up to 170 and was told it spread throughout out the body and that was it and I get those are similar stories you have heard and I'm looking at these studies which are coming out and obviously you, this has just come out, you've just published this in the conservative woman as of when we're recording actually on the 15th, but you need studies I guess to analyse the data and put it together it's one thing having the individual stories, but these studies seem to be telling you what you already had heard in your individual patients. Yes, indeed. I mean, we've been really waiting for proper studies like this, and there seemed to be a real hesitation. I mean, I told everybody who criticized me, well, go away and look at it. You're sitting on the data. You're head of trusts. You're head of of MRC, CRUK, all these things. That's your job. It's not my job. My job is to be the whistle-blower. But as we know, whistle-blowers in the health service are persecuted, and it would have seemed to be the same in science and everything as well. It's been going on a long time. I was reminded yesterday that Semmelweis, who was the first person to point out that the dreadful sepsis deaths in the maternity ward were due to the fact nobody washed their hands, and if you washed their hands, you didn't get it. All his colleagues turned around and said, you're a lunatic, and had him locked up. I mean, I don't think things have changed with this pandemic at all. That's exactly what's going on. It's the death of science. nobody wants to discuss the data whether it be the origin of the virus whether it be with a pandemic it's a good or bad thing whether it be that masks are a good or bad things or that whether we should have been able to early treat as you would any respiratory virus with a good boost of vitamin D, soluble aspirin, intranasal interferon, beclamide, if it goes to the chest all these things I believe, and ivermectin which having looked at all the data, I can understand now why nobody in the establishment wanted it anywhere near a COVID patient because it worked and it saved them and there would be no need for any vaccine whatsoever and Fauci demonized it as a horse de-wormer when it is probably one of the most effective drugs in humans ever in the history of medicine, because it It prevents all sorts of things, river blindness and the liver, all the flukes, et cetera, in Africa and Asia. And may well be a major reason why the incidence of COVID deaths in these places was so low, because they were all on ivermectin and getting good vitamin D, of course. I've just spoken out as these studies are coming out, and we'll put the link to the Japanese study in the description. Of course, it's in that article. As more and more people have spoken out, are you seeing more of your colleagues going public on it? Because surely when the studies are coming out, the data is released, then that's proving what has happened. And therefore, you will get more and more people from the medical community who actually are speaking up and saying, yeah, this is correct. Do you think that will happen? Well, I hope so. I hope so. So the ones that spoke up and said, you're correct, all said, by the way, we've been told to shut up too and not upset the patients. This is like it was a central script written somewhere because they told me the same in America, Canada, Australia, Europe and Britain, that to be quiet. I got carpeted for pointing all these things out and said I was breaking NHS guidelines. And this would go down on my thing as breaking rules. I said, I don't give a damn. All I'm doing is making sure I do no harm. I suggest you do the same. NHS is causing more harm. I think the NHS, one of the reasons it's crippling, it's spending so much time treating the side effects of the vaccine program. And they won't admit it, of course. And I've been doing some medical legal instances where people have clearly been damaged by the vaccine and none of the people concerned will admit it. They just say coincidence. It's just like a tape. And I've spoken to lots of people who had very bad vaccine and had just been really badly treated. They go out of the way to make sure it's not enough for compensation. And I hadn't realized how many people had lost their jobs in the UK because they refused to get vaccinated or they refused to get the booster because they had had such bad bad side effects from the first two. How can you possibly justify that? If you have a bad reaction to a drug, you don't take it again. You don't take another dose and hope it's not as bad this time, which seems to be the NHS and the government's attitude to it. Yeah. Another part is the cancer issue, and obviously seems to be speeding up cancer much faster. That's certainly the people I've talked to. But the other side, and a lot of the media reports have been a shocking cancer amongst younger people. And the journalists, right, they have no idea why…. Yes, they do. this has been happening recently but I mean tell because, it's that concern you think cancer is something you get maybe later on in life but this is happening younger, this changes the very nature of what that is the impact on society. Yes I mean we have seen and there there is a paper showing that there is a real increase in patients under 44. I think it's 19 to 44 a massive increase in cancers and particularly abdominal cancers. So colorectal. We were seeing this before, by the way, in young people in this country, obviously not in Japan. And so I've always said it must be something to do with the diet is driving this, and so do most people. But it seems to have accelerated since the vaccine program came on. But we're seeing all the others. I mean, I was really surprised. We're seeing oesophageal cancer, biliary, liver, pancreatic, upper and lower bowel, weird ones like appendix cancers. You know, incredibly rare. I was contacted by a fellow who said that he'd seen about one of these. He runs a colorectal surgery and he's seen about one in the last five years. And he said, I've seen 13 recently, and they'd all had the vaccine. They were all in young people. So, I mean, so when people get cancers, unusually unexpected. The first thing you should do is say, why? Do they have something in common? Well, they do. The vast majority, again, not all of them, because there's a background incidence, have all had the vaccine or a booster. And that to me is stop the bloody program now, you know instead I'm being told to go and get my spring booster what planet are these people on? This is, since you've spoken up nearly or 18 months or 21 months ago I've seen more and more people write about it, is this the end then of this worldwide experiment of this new type of technology, this mRNA which is massively backfired or is it just how Big Pharma work and then they come up with the mRNA now to fix cancer which is the the latest thing we've heard. Yeah, well, they were always working on that. And I actually, you know, when people tell me I'm a clinician and I don't know what I'm talking about and to shut up, I tell them I know a darn sight more than they do. And especially about the dangers of messenger RNA vaccine, because I was on a scientific advisory board for a company whose subtitle was the messenger RNA vaccine company for five years and I left about seven years ago and they were targeting cancer and they didn't get through, BioNTech had the same thing. Big Pharma and whatever's behind them at far more sinister, has used this pandemic and I mean, when it started I wouldn't even have thought along these lanes. I honestly think it was planned, it's like it was planned to get the messenger rna out, when you go back and you look at the Manhattan project for vaccines and world health, their big issue was why do we make all these vaccines? If we don't have a pandemic we won't make any money, we'll lose money so this really looks like it was all planned, why did Moderna have a patent on sars-2 in February 2019? Why did the German government go ahead and fund an an enormous big vaccine facility in Marburg to produce messenger RNA, long before they were anywhere near being approved. It sounds like the whole thing was part of some sinister plan. And that's what I find really, really concerning. And I've spoken up and on the record. I think the messenger RNA vaccines are an absolute disaster, should be banned. They should be completely, utterly banned. And they are what they say on the till in the early BN Biotech preparations for Pfizer, they have COVID vaccine-gene therapy. Well, that was honest. You don't use gene therapy on a pandemic that kills less than 1% of people. And then you go ahead with the plan, when you know that the people who did die had an average age in the UK of 82, whereas average age of anybody else dying of anything else was 81. So the logical thing for a statistician was to go around and prepare COVID and spray it all around the population and tell them they'll live an extra year longer, because you've got I mean, being very cynical about it. But why would you? You shouldn't do it. Chris Whitty occasionally said some sensible things, but then went on to being beheaded or whatever it is and go along with this madness. He said, you can't use a vaccine unless you've got a death rate of 30% in the main population. You can't justify it if you haven't got the safety data. Why did he not stand up when it was 1% and stop it? Could it be something to do with shut up and you'll get your rewards in the honours list which they all did these people all of them, Vallance, Whitty and all these, I was going to say goons from SAGE, I'll say that again I do, I disagreed with them totally and utterly and even the people working with the vaccines from Oxford, the Astra Zeneca, they all got knighthoods, damehoods everything long before there was any evidence it was of any any benefit. It's unbelievable. When these studies come out, a lay person like myself will think this then starts a catalyst of looking at other countries and wanting the data. But then the flip side is you realize the difficulty of data, and you touched on that. I think you had mentioned that whenever I saw you speak at Andrew Bridgen's event the end of last year in Parliament, the lack of data. It seems like there is British data. there is Israeli data and there does seem some Japanese data. Many other countries seem to have a complete void, but the UK government don't even want to release any of the data. Will this force them to release it? Will this mean there are possible financial penalties? I mean, these companies getting sued? Where does this go whenever one country brings out a study like this, which is so comprehensive? Well, I think you'll get other countries that will do it. I really do. I mean, Australia, who behaved appallingly during the pandemic, I mean, they were run by a bunch of, not just clowns, but really ghoulish clowns who seem to relish in power and locking down and God knows what else, have mandatory vaccines. Well, at least they have. They've had a lot of revolt over this, and they finally had a formal Australian Commission on Excess Deaths. And I've been asked to give evidence for it as have some other people who've raised their voice and we'll make it very very clear what's going on, some of the senators now in Australia know exactly what was going on and they're baying for blood as it were and the thing that I'm baying for, why were the people like me in Australia and I worked in Australia for seven years by the way, I did flying doctor for a year and I did internal medicine and oncology. I know it very very well, why did these doctors who thought like me, I'm going to look after the patients, this, that and the other, they got struck off if they they wouldn't go along with this madness. I mean, it's unbelievable. It was inhumane. And at least that commission is going to uncover it. I think our COVID inquiry is a whitewash to kick the can down the road for so long. By the time it comes to the conclusions, nothing to see here, nobody, no one person was guilty. There'll be lessons to learn. No, there won't be any lessons to learn unless they hold people to account, unless we withdraw from the WHO, this madness, this treaty they want us to sign up to, once they're all signed up, they release the next pandemic and they will have another round of vaccines for you. I mean, I thought this was absolute madness to even think like that. But George Orwell saw it all 70 years ago, 70 years plus. And I mean, it's just unbelievable. I re-read 1984 and Animal Farm when I went on holiday recently. They had a package, and I'd read them 40, 50 years ago, a long time. If I hadn't have read them, I'd have thought, oh, somebody's seen through the lockdown and written these in lockdown as to where it could lead once you give the power to the governments to bully the thing. Yeah, it's incredible. They could have been written in the lockdown, but he wrote them 50 years ago. He saw what was coming. Obviously, it was about the communist model coming out of Russia and the implications. But I never thought I would live long enough to see democracy being destroyed by the same tentacles of control that emerged due to the COVID. And it's given them a power to interfere in everything else. I mean, a power to block all kinds. I've lost my faith totally in justice in the UK, probably worldwide. The Postmaster scandal was unbelievable. when the guy was told you're the only one, I remember that's what I was told when I made a great fuss, you're the only one, it transpires there were dozens and dozens of us who made, said the same thing to the government, they ignored, there were hundreds and hundreds of postmasters who said the same thing that they ignored and now, you know we're going we're having the same absolute nonsense over climate control. I mean I went and researched climate control, I didn't have to do much research before I realized that the data is very clear out there that carbon dioxide rises when the world warms. And it is actually something that's trying to do something good about it. And it does. It's a heavy gas, falls to the ground, encourages plant growth, tree growth, which produces more oxygen. It is. It's like a controller. It's like a thermostat. It is not the cause. And you've got all these morons, and I use the word advisedly, and people like Ed Miliband should springs to mind this guy is a total moron, who thinks that if you stop the co2 from the cars, this, that and the other, you'll save the world from global warming, it won't make one iota difference and if you really succeeded in lowering co2 significant, you would actually start extinguishing life they don't seem to understand any basic biology at all and yet these morons are running our parliament, running our lives and they are impoverishing everybody on this planet. I saw my energy bill even though we tried very hard, it's absolutely ludicrous and it's even worse knowing it is five times higher than if I was in the United States where at least they've got some pragmatism with regards is, we can't do everything in the solar and wind we're going to need our oil and gas and by the way it's beneath us, ours is beneath us but we've basically said we're not going to use it and so we're dependent on China who's polluting the world to death, it's unbelievable. I think many people have had their eyes open to many of these issues over the last couple of years of COVID tyranny. Professor Dalgleish, I'm honoured really to have you on, it's wonderful to hear your thoughts and your writings, it's good to delve into them, people can get the Conservative Woman, but thank you so much for the stand you've taken and thank you for sharing your thoughts with us today. Right. Well, thank you very much for having me. But just remember, we've written an enormous amount of this up in The Death of Science, which is available on Kindle, Amazon, and is multi-author. And it's got contributions from Karol Sikora, Sir Richard Dearlove, Clare Craig, Ros Jones. I mean, I'm really proud that we've been able to really put the gauntlet down, that this government and the world's governments and the scientists and the institutions and the medical profession have killed science. We have to do everything we can to rectify that. Thank you. And the viewers and listeners can get that. The links will be in the description. So however you're watching, however you're listening, you can just click on that. So, Professor, once again, thank you for your time today. Cheers. Thank you.

James acquired the developer of the patented FIT (Food Inflammation Test) Test which is the first assay to identify IGG1-4 and C3d, the inflammation marker simultaneously for 176 foods, colorings, and additives. The ability to help reduce inflammation by personalizing a patient's diet has the promise to reduce symptoms in cardiovascular, diabetes, IBS and other autoimmune diseases as well as the opportunity to aid in weight loss. The company has expanded the product range to include a FIT 22, FIT 132 and FIT 176 assays and recently launched Gut Barrier Panel.The company has grown from 5 to just over 5,000 providers ordering the test in the USA and internationally through our distribution and Laboratory partners in Asia,Europe and Latin America. The company's facilities include an ISO and FDA registered manufacturing facility, 2 CLIA High Complexity laboratories, Sales and Marketing and Logistic Capabilities. During the COVID Pandemic KBMO was one of the first commercial labs offering antibody testing and PCR testing to providers.

AHCC shows promise in clearing HPV Patients in the placebo group received a placebo for 12 months. The study found that 14 of 22 patients (63.6%) in the treatment arm became HPV-negative AHCC® Supplementation to Support Immune Function to Clear Persistent Human Papillomavirus Infections Front. Oncol., 22 June 2022 | https://doi.org/10.3389/fonc.2022.881902 https://www.eurekalert.org/news-releases/956667#.YrUfbtgh65k.wordpress #HPV #AHCC #HumanPapillomavirus #HPV #AHCC #HumanPapillomavirus #lentinula #ifn #igg1 #nk #infection #mushroom #immune human papillomavirus, HPV, AHCC, NEGATIVE, active hexose correlated compound, lentinula edodes mycelia, MUSHROOM, INFECTION, IMMUNE, ONCOLOGY, interferon alpha, interferon beta, IFN, interferon gamma, IFN, IgG1, T lymphocytes, natural killer cell levels, NK --- Support this podcast: https://anchor.fm/ralph-turchiano/support

AHCC shows promise in clearing HPV Patients in the placebo group received a placebo for 12 months. The study found that 14 of 22 patients (63.6%) in the treatment arm became HPV-negative AHCC® Supplementation to Support Immune Function to Clear Persistent Human Papillomavirus Infections Front. Oncol., 22 June 2022 | https://doi.org/10.3389/fonc.2022.881902 https://www.eurekalert.org/news-releases/956667#.YrUfbtgh65k.wordpress #HPV #AHCC #HumanPapillomavirus #HPV #AHCC #HumanPapillomavirus #lentinula #ifn #igg1 #nk #infection #mushroom #immune human papillomavirus, HPV, AHCC, NEGATIVE, active hexose correlated compound, lentinula edodes mycelia, MUSHROOM, INFECTION, IMMUNE, ONCOLOGY, interferon alpha, interferon beta, IFN, interferon gamma, IFN, IgG1, T lymphocytes, natural killer cell levels, NK --- Support this podcast: https://anchor.fm/ralph-turchiano/support

To start using Tab for a Cause, go to: http://tabforacause.org/minuteearth2 You might already know that proteins are a fundamental part of your diet, but they're much more than that. LEARN MORE ************** To learn more about this topic, start your googling with these keywords: - Amino acids: are organic compounds that contain amino (–NH2) and carboxyl (–COOH) functional groups, along with a side chain specific to each amino acid. - Proteins: are macromolecules composed of one or more long chains of amino acid residues. Most proteins fold into unique 3D structures. The shape into which a protein naturally folds is known as its native conformation. - Alpha helix (α-helix): is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues earlier along the protein sequence. - Beta sheet (β-sheet): is a common motif of the regular protein secondary structure and consists of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet. - Ribbon diagrams: are 3D schematic representations of protein structure that shows the overall path and organization of the protein backbone in 3D. Ribbon diagrams are generated by interpolating a smooth curve through the polypeptide backbone. α-helices are shown as coiled ribbons or thick tubes, β-strands as arrows, and non-repetitive coils or loops as lines or thin tubes. CREDITS ********* Ever Salazar | Co-Writer, Narrator, Illustrator and Director David Wych | Co-writer and Consultant Aldo de Vos, Know Art | Music MinuteEarth is produced by Neptune Studios LLC https://neptunestudios.info OUR STAFF ************ Sarah Berman • Arcadi Garcia Rius • David Goldenberg Julián Gustavo Gómez • Melissa Hayes • Alex Reich Henry Reich • Peter Reich • Leonardo Souza Ever Salazar • Kate Yoshida OUR LINKS ************ Youtube | https://youtube.com/MinuteEarth TikTok | https://tiktok.com/@minuteearth Twitter | https://twitter.com/MinuteEarth Instagram | https://instagram.com/minute_earth Facebook | https://facebook.com/Minuteearth Website | https://minuteearth.com Apple Podcasts| https://podcasts.apple.com/us/podcast/minuteearth/id649211176 OTHER CREDITS & REFERENCES ********************************** Goodsell, David (2006). Visual Methods from Atoms to Cells. Structure 13, Issue 3:347-354. doi:10.1016/j.str.2005.01.012 Protein 3D images created using Mol* (https://molstar.org/) and structure data from RCSB PDB (https://www.rcsb.org/) Mol* (D. Sehnal, A.S. Rose, J. Kovca, S.K. Burley, S. Velankar (2018) Mol*: Towards a common library and tools for web molecular graphics MolVA/EuroVis Proceedings. doi:10.2312/molva.20181103) Villin folding trajectory by Stefan Doerr - https://figshare.com/authors/Stefan_Doerr/748688 Clathrin Structure (PDB ID: 3IYV) Fotin, A., et al (2004). Molecular model for a complete clathrin lattice from electron cryomicroscopy. Nature 432: 573-579. doi:10.1038/nature03079 Immunoglobulin Structure (PDB IDs: 1IGT & 1IGY) Harris, L.J., et al (1998). Crystallographic structure of an intact IgG1 monoclonal antibody. J Mol Biol 275: 861-872. doi:10.1006/jmbi.1997.1508 ATP Synthase Structure (PDB IDs: 5ARE, 5ARI & 5FIL) Zhou, A., et al (2015). Structure and conformational states of the bovine mitochondrial ATP synthase by cryo-EM. ELife, 4. doi:10.7554/eLife.10180 RCSB PDB Molecule of the Month by David S. Goodsell (The Scripps Research Institute and the RCSB PDB) - https://pdb101.rcsb.org/motm/72 Photosystem II (PDB ID: 5XNL) Su, X., et al (2017). Structure and assembly mechanism of plant C2S2M2-type PSII-LHCII supercomplex. Science 357: 815-820. doi:10.1126/science.aan0327 Ribonuclease (PDB ID: 2AAS) Santoro, J., et al (1993). High-resolution three-dimensional structure of ribonuclease A in solution by nuclear magnetic resonance spectroscopy. J Mol Biol 229: 722-734. doi:10.1006/jmbi.1993.1075 Myosin (PDB ID: 1B7T) Houdusse, A., et al (1999). Atomic structure of scallop myosin subfragment S1 complexed with MgADP: a novel conformation of the myosin head. Cell 97: 459-470. doi:10.1016/s0092-8674(00)80756-4

  Vidcast:  https://youtu.be/7VEwuryRJ7Y   The FDA just granted an emergency use authorization, the prized EUA, for Lilly’s IgG1 monoclonal antibody called Bamlanivimab.  This now joins the  Regeneron dual antibody cocktail as early treatment for CoVid.   Thing is, though, there are many catch-22s about bamlanivimab.  It must be given immediately after symptom onset when patients are at their most contagious and a danger to others.  It’s not for hospitalized patients or for those requiring oxygen.  Bamlanivimab requires 3 hours for IV infusion, its tricky to prepare and requires refrigeration, and it has serious side effects like anaphylaxis.  The worst problem: it’s in short supply and there’s only about 2 week’s worth in existence.   https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibody-treatment-covid-19   https://blogs.jwatch.org/hiv-id-observations/index.php/bamlanivimab-hard-to-pronounce-even-harder-to-give/2020/11/15/   #covid #bamlanivimab #monoclonalantibody  

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  

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. Michael Levy, associate professor of neurology at Johns Hopkins University. When we met in his office, he told me about his work on the role of T cells in neuromyelitis optica, or NMO. Finding antibodies to aquaporin-4 is indicative of NMO. But when Dr. Levy used aquaporin-4 reactive T cells, they could induce NMO in a mouse model, giving a clue to the role of T cells in the disease, and possibly opening up a new therapeutic avenue.   Interviewer – Dan Keller What's different about this approach than what has been thought of previously?   Interviewee – Michael Levy In neuromyelitis optica, there is the thought that the disease involves an antibody, the anti-aquaporin-4 antibody, that that antibody is involved in causing the disease. And what we demonstrated in this model is that we could recreate the disease simply by developing T cells against aquaporin-4. It's the exact same target as the antibody, but instead of using the antibody to exacerbate disease, we use T cells. And it works really well and causes optic neuritis and transverse myelitis, just like in the patient.   MSDF Can you briefly describe your method?   Dr. Levy We raised T cells in mice that don't have aquaporin-4. These mice see aquaporin-4 as a foreign antigen and mount an aggressive immune response against them, and we harvest those T cells from that animal. And what we do is we polarize them. We basically turn them into more aggressive types of immune cells in a dish. And then we transfer those T cells to a naïve mouse that does contain aquaporin-4. And those T cells attack the aquaporin-4, and it does so only in the optic nerves and the spinal cord and also a little bit in the brain.   MSDF But aquaporin-4 is distributed more widely than that in the body.   Dr. Levy That's correct. Actually, there's a higher level of aquaporin-4 in the lung, stomach, kidneys, muscle. Many tissues contain aquaporin-4, but the T cells decide which aquaporin-4 to attack. They are a thoughtful type of cell, and for whatever reason, and this is true in the human, too, the T cells only decide to go for those specific tissues.   MSDF How does a mouse with aquaporin-4 get to an age where you can actually get these T cells out of it? What's the use of aquaporin-4 if they really can survive without it?   Dr. Levy It's amazing that these knockout mice, they don't have any aquaporin-4, are completely viable. There are some abnormalities in function under certain stressful conditions, like stroke or brain trauma, but for the most part, they live normal lives. They must have a good compensatory mechanism that they don't need aquaporin-4, and that's fortunate for us because we can create these animal models.   MSDF When you transferred these T cells to wild-type mice, what did you see?   Dr. Levy Eight days after the transfer, the first thing we noticed is that the mice started blinking and the eyes became sunken into the head, and that's a sign of severe optic neuritis. And then two days later, they had a dragging tail. And a day after that, their hind limbs were paralyzed, and that indicated transverse myelitis.   MSDF What's the role of the antibody if you can induce the disease with the T cell? And does the antibody in itself without T cells have an effect?   Dr. Levy We looked at that, and what we found is that the antibody by itself has absolutely no effect. But in the context of a T cell attack, it can exacerbate the disease, and it does lend specificity to the pathology when you look at it under a microscope. If you add the antibody, there is more aquaporin-4 damage, and it recruits compliment, which causes that damage. So that's really the role of the antibody.   MSDF Can you induce the antibody without T cells? Essentially is aquaporin-4 a T-dependent antigen?   Dr. Levy We think it is, and that's based on the type of antibody it is. The antibody in a human is what's called an IgG1 subtype, which is a T cell-dependent subtype. And that bears out in the animal models as well.   MSDF So the antibody is really an enhancer in the disease as opposed to an initiator?   Dr. Levy That's our thinking. It's not just an enhancer, but also a biomarker of the disease. And maybe in some patients, the antibody is not as harmful, but more of just a biomarker.   MSDF What's the significance of these findings, especially as it relates to human conditions?   Dr. Levy We're always looking for a new target to treat NMO patients, and there were some who were thinking that we should be targeting the antibody to try to either remove it or soak it up somehow. And maybe our model suggests that we should be targeting the T cells. And if there were ways that we could retrain or reeducate those T cells not to attack aquaporin-4 and create a really specific therapy, then we could avoid these broader immunosuppressive therapies that are necessary now to treat these patients.   MSDF Since you have a defined antigen in this case, and I assume you can make some of it, do you have any hope of being able to induce high-zone tolerance using it?   Dr. Levy That is our goal, and we've partnered with a company now to try to create a vaccine therapy using that antigen target. Again, in the same way that a T cell is turned pathogenic with this antigen, we can then retrain that T cell to be tolerized to it. And so we're hoping to apply that sort of technology to humans.   MSDF Now you're coming in at a late stage of the disease. I mean, someone has to present with the disease for you to want to treat it. So really, you can't prevent it. This would be a therapeutic vaccine, not a preventative vaccine?   Dr. Levy Correct. A vaccine therapy more along the lines of retraining than preventing and preparing. Correct.   MSDF Now this applies to NMO, but what about applying it to MS? With NMO, you've got a defined antigen.   Dr. Levy That's exactly right. And with NMO, there isn't what we call antigen spreading, which is where the immune system decides instead of targeting that one antigen, it's going to spread. The epitope is going to spread to other areas of myelin and maybe other components of the central nervous system. With NMO, the antigen is really focused on aquaporin-4, and so that's our advantage. And in MS, there are a lot more targets, and it's probably more of a heterogeneous disease. It would be harder to develop a vaccine therapy for MS.   MSDF Where do you go from here? What's next?   Dr. Levy Next is demonstrating that the mouse model responds to a vaccine therapy approach. We'd like to show that the T cells can be stopped, even when they're pathogenically targeting the aquaporin-4. Transferred into a mouse, we need to demonstrate that a vaccine therapy can prevent their attacks.   MSDF Have you looked or demonstrated T cell receptors specifically for aquaporin-4 fragments?   Dr. Levy We're looking at that now. We're looking in human subjects. We isolate their T cells, and we're looking for a response to certain epitopes of aquaporin-4. That has been done by other groups, but we're looking for specifically pathogenic epitopes now.   MSDF Is there any thought towards some sort of suicide experiment where these T cells that have become activated could then be killed because they're proliferating?   Dr. Levy There is a company in Houston called Opexa Therapeutics. They're doing something similar to that. They're picking out patients' T cells that are reactive against aquaporin-4 and inducing apoptosis so that when these T cells are reintroduced to the body, there is a tolerization. So it is kind of the same thing that you're suggesting. And they are hoping to launch a trial like this by next year.   MSDF Is there anything we've missed or important to add?   Dr. Levy What I'd like to emphasize again is that by focusing on the T cells, we can really hone in on the very upstream early event and really specifically treat…I don't want to use the C word to say cure, but it's really focusing on the source of the problem, rather than treating all the downstream consequences, which is what we do now. So I think our approach has that specific advantage.   MSDF An advantage over a more global nonspecific immunosuppression?   Dr. Levy Exactly, which is what we're doing now.   MSDF Very good. Thanks.   Dr. Levy Thank you.   [transition music]   MSDF Thank you for listening to Episode Ninety-five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   [outro music]   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   For Multiple Sclerosis Discovery, I'm Dan Keller.

Sandro De Falco, Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, Naples, ITALY speaks on "Target-independent suppression of angiogenesis by human IgG1 antibodies and IVIg via FcyRI".This seminar has been recorded by ICGEB Trieste

Myelin Oligodendrocyte Glycoprotein (MOG) is one of the few proteins known to be localized on the outermost sheath of central nervous system (CNS) myelin. Due to this localization, MOG is accessible to antibodies. Anti-MOG antibodies are demyelinating and enhance clinical symptoms in a number of animal models of CNS inflammation. Autoantibodies recognizing conformationally intact MOG are found in different inflammatory diseases of the CNS, but their antigenic epitopes had not been mapped. In this work, 9 variants of MOG with an intracellular enhanced green fluorescent protein (EGFP) tag were expressed on the cell surface of human HeLa cells and used to analyze sera from 111 patients (104 children, 7 adults), who had antibodies recognizing cell-bound human MOG. These patients had different diseases, namely acute disseminated encephalomyelitis (ADEM), one episode of transverse myelitis or optic neuritis, multiple sclerosis (MS), anti-aquaporin-4 (AQP4)–negative neuromyelitis optica (NMO), and chronic relapsing inflammatory optic neuritis (CRION). The expression levels of the mutants were comparable and cells with a defined expression level (fluorescence intensity in the EGFP channel of 102-103) were gated. Each MOG-mutant was recognized by at least one MOG-specific mAb. This allowed the comparison of binding to the different mutants. In order to assess the reproducibility of the system, binding of the 111 sera to the mutants was analyzed up to three times in independent experiments, yielding a very good reproducibility of the binding percentage with an absolute SD of 7.8% in the case of low recognition of a mutant and a relative SD of 20% in the case of high recognition of a mutant. The applied variants of MOG gave insight into epitope recognition of 98 patients. All epitopes identified in this work were located at loops connecting the ß-strands of MOG. The immunodominant epitope of human anti-MOG antibodies was at the membrane-proximal CC’-loop containing aa42, which is not present in rodent MOG. This loop was recognized by about half of all patients. Overall, seven epitope patterns were distinguished, including the one mainly recognized by mouse mAbs at the FG-loop around aa104. Evidence from mouse models of CNS inflammation shows that anti-MOG antibodies recognizing different epitopes can be demyelinating and thus pathogenic. This suggests that not only those antibodies recognizing the same epitope of MOG as the pathogenic mAbs (i.e. the FG-loop), but also the ones recognizing the CC'-loop are pathogenic in humans, as both epitopes allow for the recognition of cell-bound MOG. In half of the patients, the anti-MOG response was directed to a single epitope. To analyze the effect of glycosylation on the recognition of MOG by human autoantibodies, a “non-glycosylation mutant” N31D was made. Digestion with PNGaseF and Western blot analysis confirmed that N31 was the only used N-glycosylation site of the MOG constructs in HeLa cells. Glycosylation of MOG was not needed for antibody binding, but 8% of the patients recognized deglycosylated MOG at least two-fold better. The epitope specificity was not linked to certain disease entities. The individual epitope recognition patterns stayed constant in 11 analyzed patients over an observation period of up to 5 years without evidence for intramolecular epitope spreading. Some patients with acute syndromes had anti-MOG IgG at disease onset, but rapidly lost their anti-MOG IgG reactivity. These patients were able to generate a long-lasting IgG response to measles and rubella virus vaccine indicating that the loss of anti-MOG reactivity was not reflective of a lack of capacity for longstanding IgG responses. Human anti-MOG antibodies are mainly of the IgG1 isotype, which can activate complement and antibody dependent cellular cytotoxicity. Upon binding to MOG in the CNS, human anti-MOG antibodies are hence expected to cause demyelination. Transfer experiments with purified human anti-MOG antibodies have not been performed yet. The fact that the majority of human anti-MOG antibodies did not recognize rodent MOG has implications for animal studies. Using the described assay will help to identify patient samples appropriate for these transfer experiments and finally lead to the formal proof of the pathogenicity of human anti-MOG antibodies. This work also gives important information for future detection of potential mimotopes and the development of anti-MOG antibody detection assays and might pave the way to antigen-specific depletion.

Background: Epithelial cell adhesion molecule (EpCAM) is frequently and highly expressed on human carcinomas. The emerging role of EpCAM as a signalling receptor and activator of the wnt pathway, and its expression on tumor-initiating cells, further add to its attractiveness as target for immunotherapy of cancer. Thus far, five conventional monoclonal IgG antibodies have been tested in cancer patients. These are murine IgG2a edrecolomab and its murine/human chimeric IgG1 antibody version, and humanized, human-engineered and fully human IgG1 antibodies 3622W94, ING-1, and adecatumumab (MT201), respectively. Here we compared all anti-EpCAM antibodies in an attempt to explain differences in clinical activity and safety. Methods: We recombinantly produced all antibodies but murine edrecolomab and investigated them for binding affinity, EpCAM epitope recognition, ADCC and CDC, and inhibition of breast cancer cell proliferation. Results: ING-1 and 3622W94 bound to EpCAM with much higher affinity than adecatumumab and edrecolomab. Edrecolomab, ING-1, and 3622W94 all recognized epitopes in the exon 2-encoded N-terminal domain of EpCAM, while adecatumumab recognized a more membrane proximal epitope encoded by exon 5. All antibodies induced lysis of EpCAM-expressing cancer cell lines by both ADCC and CDC with potencies that correlated with their binding affinities. The chimeric version of edrecolomab with a human Fc gamma 1 domain was much more potent in ADCC than the murine IgG2a version. Only adecatumumab showed a significant inhibition of MCF-7 breast cancer cell proliferation in the absence of complement and immune cells. Conclusion: A moderate binding affinity and recognition of a distinct domain of EpCAM may best explain why adecatumumab showed a larger therapeutic window in cancer patients than the two high-affinity IgG1 antibodies ING-1 and 3622W94, both of which caused acute pancreatitis.

IgG1 Antibodies to Acetylcholine Receptors in ‘Seronegative' MG by Angela Vincent, MD

An interview with Angela Vincent, MD, co-author of "IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. " Brain. 2008 May 31. Interviewed by Ted Burns, MD, and Robert Pascuzzi, MD.

An interview with Angela Vincent, MD, co-author of "IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. " Brain. 2008 May 31. Interviewed by Ted Burns, MD, and Robert Pascuzzi, MD.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). Myelin antigen(s) specific T cells, B cells, and antibodies are thought to play a role in the pathogenesis of MS. While the influence of autoantigenspecific CD4+ T cells has been extensively studied in animal models, the relevance of autoantigen specific B cells and their interactions with pathogenic T cells are largely unknown. The original aim of the present study was to create a new mouse model with which to investigate the interaction of myelin autoantigen specific B and T cells and their role in MS pathogenesis. The study was further expanded to analyze the nature and triggers of spontaneous disease and similarity of the mouse lesion pattern to that in human disease. The double-transgenic mouse (“Devic mouse”) strain presented here contains myelin oligodendrocyte glycoprotein (MOG)-specific T as well as B cells. A significant proportion (>50%) of these mice showed spontaneous experimentalautoimmune encephalomyelitis (EAE)-like disease at a young age. In contrast, all single transgenic littermates were free of clinical disease. Spontaneous EAE requires both MOG-specific T and B cells, since the breeding of MOG-specific Ig heavy chain knock-in mice with ovalbumin specific T cell receptor (TCR) transgenic mice did not develop any disease. Histological analysis of the CNS of affected mice revealed restricted localization of lesions in the spinal cord and optic nerves as well as severe demyelination and axonal damage that spared brain and cerebellum. The inflammatory infiltrates were predominantly composed of macrophages and CD4+ T cells, but occasionally also eosinophils. This peculiar localization of the demyelinating lesions and infiltration profile differ from classic EAE and is reminiscent of Devic’s neuromyelitis optica, a variant of classic MS in humans. It is not well understood what triggers the initiation of spontaneous EAE. The microbial environment does not significantly affect the clinical disease. Stimulation of the innate immune system with toll-like receptor (TLR) ligands or depletion of putative regulatory cells did not significantly affect EAE development. The (re-)activation of lymphocytes in sick Devic mice mainly occurs in the CNS without evidence of priming in the peripheral lymphoid organs. MOG-specific B and T cells cooperate by means of several mechanisms. MOGspecific B cells, which bind MOG but not the immunodominant peptide MOG 35-55 via their surface immunoglobulin (Ig), efficiently presented even high dilutions of MOG to T cells. This resulted in the enhanced proliferation of T and B cells as well as rapid activation. Stimulated T, but not B cells, secreted large amounts of Th1 cytokines IFNg and IL-2 along with small amounts of Th2 cytokine IL-5. In addition, MOG-stimulated T and B cells expressed a set of co-stimulatory molecules, which further help to modulate the proliferation and activation. Surprisingly, the doubletransgenic Devic mice, but not their single transgenic littermates, had high titers of MOG-specific IgG1 antibodies in the serum, which indicates a previous encounter with antigen in vivo. However, similar MOG-specific serum IgG1 titers were present irrespective of the clinical status. The transfer of EAE by Devic splenocytes in immunodeficient mice or by bone marrow reconstitution in wild-type mice further supported the in vivo cooperation of MOG-specific T and B cells to induce spontaneous EAE. In summary, Devic mice show several salient features that are important for study of the pathogenic mechanisms of CNS autoimmunity. As a model of spontaneous autoimmunity, they may allow us to study the triggering factors of autoimmunity as well as the factors that determine restricted infiltration of immune cells into the CNS.In addition, the model may be useful for validating novel therapies for autoimmune CNS diseases.

Background: Recent epidemiological studies have shown that growing up on a traditional farm provides protection from the development of allergic disorders such as hay fever and allergic asthma. We present experimental evidence that substances providing protection from the development of allergic diseases can be extracted from dust collected in stables of animal farms. Methods: Stable dust was collected from 30 randomly selected farms located in rural regions of the Alps (Austria, Germany and Switzerland). The dust was homogenised with glass beads and extracted with physiological sodium chloride solution. This extract was used to modulate immune response in a well established mouse model of allergic asthma. Results: Treatment of mice by inhalation of stable dust extract during sensitisation to ovalbumin inhibited the development of airway hyperresponsiveness and airway eosinophilia upon challenge, as well as the production of interleukin 5 by splenocytes and of antigen specific IgG1 and IgE. Dust extract also suppressed the generation of human dendritic cells in vitro. The biological activity of the dust extract was not exclusively mediated by ipopolysaccharide. Conclusions: Stable dust from animal farms contains strong immune modulating substances. These substances can interfere with the development of both cellular and humoral immunity against allergens, thus suppressing allergen sensitisation, airway inflammation, and airway hyperresponsiveness in a murine model of allergic asthma.

Psoriasis is a chronic, incurable, auto-immune disorder with cutaneous manifestations. New evidence on the central role of the immune system in the pathogenesis of psoriasis increasingly provides insight into pathogenic steps that can be modulated to provide disease control. Numerous biological therapies are in various stages of clinical development, with expectation of providing enhanced safety and efficacy over currently available psoriasis therapies. Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a novel targeted T-cell modulator that inhibits multiple steps in the immune cascade that result in the production and maintenance of psoriatic plaques, including initial T-cell activation and T-cell trafficking into sites of inflammation, including psoriatic skin, with subsequent reactivation in these sites. This article reviews the pharmacodynamic, pharmacokinetic and clinical effects observed during phase I, II and III efalizumab trials in patients with moderate to severe chronic plaque psoriasis. Copyright (C) 2004 S. Karger AG, Basel.

The establishment of hybridomas after fusion of X63-Ag8.653 mouse myeloma cells and splenocytes from mice hyperimmunized against human astrocytomas is presented. The animals were primed with 5 × 106 chemically modified uncultured or cultured glioma cells. Six weeks after the last immunization step an intrasplenal booster injection was administrated and 3 days later the spleen cells were prepared for fusion experiments. According to the specificity analysis of the generated antibodies 7 hybridoma products (MUC 7-22, MUC 8-22, MUC 10-22, MUC 11-22, MUC 14-22, MUC 15-22 and MUC 2-63) react with gliomas, neuroblastomas and melanomas as well as with embryonic and fetal cells but do not recognize non-neurogenic tumors. The selected monoclonal antibodies (McAbs) of IgG1 and IgG2a isotypes are not extensively characterized but these antibodies have been demonstrated to be reactive with a panel of glioma cell lines with varying patterns of antigen distribution. Using the McAbs described above and a series of cryosections of glioma biopsies and paraffin sections of the same material as well as glioma cultures established from these, variable antigenic profiles among glioma cell populations could be demonstrated. From these results it is evident that there is not only a distinct degree of antigenic heterogeneity among and within brain tumors, but also that the pattern of antigenic expression can change continuously. Some of the glioma associated antigens recognized by the selected antibodies persist after fixation with methanol/acetone and Karnovsky's fixative and probably are oncoembryonic/oncofetal antigen(s). The data suggest that the use of McAbs recognizing tumor associated oncofetal antigens in immunohistochemistry facilitates objective typing of intracranial malignancies and precise analysis of fine needle brain/tumor biopsies in a sensitive and reproducible manner.