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This week on TRF we cover: Riots in the streets of Calgary! The little bylaw was not very well thought out. In the News Remote workers face the cold facts, they are 35% higher risk of being laid off. Salesforce joins the flood of tech industry lay offs UPS cuts management and contractors in a bid to save $1BB in costs, that is out of the $100BB in sales in 2022 In happier news, the global online recruitment market is set to reach $49.2 BB by 2030 Tip of the Week 3 simple things to improve your job ads. Shorten your sentences 3 bullet points max! Pay attention to the words you use. “Demonstrated ability” means different things to older workers than it does to younger workers Recruiting Insights Linked In XRay search options, including key fields like job title will have an impact on sourcing tools. SeekOut and hireEZ have a work around. More on skills based hiring. When 46% of workers say their formal qualifications are not relevant to what they are doing in their current job. You need to ask yourself why the fixation on that bachelor's degree. Bigger isn't better. 85% of mid-sized companies reported ZERO layoffs last year.
This week on TRF we cover: Riots in the streets of Calgary! The little bylaw was not very well thought out. In the News Remote workers face the cold facts, they are 35% higher risk of being laid off. Salesforce joins the flood of tech industry lay offs UPS cuts management and contractors in a bid to save $1BB in costs, that is out of the $100BB in sales in 2022 In happier news, the global online recruitment market is set to reach $49.2 BB by 2030 Tip of the Week 3 simple things to improve your job ads. Shorten your sentences 3 bullet points max! Pay attention to the words you use. “Demonstrated ability” means different things to older workers than it does to younger workers Recruiting Insights Linked In XRay search options, including key fields like job title will have an impact on sourcing tools. SeekOut and hireEZ have a work around. More on skills based hiring. When 46% of workers say their formal qualifications are not relevant to what they are doing in their current job. You need to ask yourself why the fixation on that bachelor's degree. Bigger isn't better. 85% of mid-sized companies reported ZERO layoffs last year.
Episode SummaryChimeric antigen receptors, or CARs, repurpose the build-in targeting and homing signals of our immune system to direct T cells to find and eliminate cancers. Although CAR-T cells have transformed the care of liquid tumors in the circulating blood, like B cell leukemia and lymphoma, CAR-T therapy has shown limited efficacy against solid tumors. To unlock the full potential of CAR-T therapies, better receptor designs are needed. Unfortunately, the space of potential designs is too large to check one by one. To design better CARs, Dan and his co-author Camillia Azimi developed CAR Pooling, an approach to multiplex CAR designs by testing many at once with different immune costimulatory domains. They select the CARs that exhibit the best anti-tumor response and develop novel CARs that endow the T cells with better anti-tumor properties. Their methods and designs may help us develop therapies for refractory, treatment-resistant cancers, and may enable CAR-T cells to cure infectious diseases, autoimmunity, and beyond.About the AuthorDuring his PhD in George Church's lab at Harvard Medical School, Dan studied interactions between bacterial transcription and translation, built and measured libraries of tunable synthetic biosensors, and constructed a new version of the E. coli genome capable of incorporating new synthetic amino acids into its proteins. He also built a high-throughput microbial genome design and analysis software platform called Millstone.As a Jane Coffin Childs Postdoctoral Fellow at UCSF, Dan is currently applying these high-throughput synthetic approaches to engineer T cells for the treatment of cancer and autoimmune disease. He is also working in the Bluestone, Roybal, and Marson labs.Key TakeawaysBy genetically engineering the chimeric antigen receptor (CAR), T cells can be programmed to target new proteins that are markers of cancer, infectious diseases, and other important disorders.However, to realize this vision, more powerful CARs with better designs are needed - current CAR-T therapies have their restraints, including limited performance against solid tumors and lack of persistence and long-term efficacy in patients.An important part of the CAR response is “costimulation,” which is mediated by the 4-1BB or CD28 intracellular domains in all CARs currently in the clinic. Better designs of costimulatory domains could unlock the next-generation of CAR-T therapies.Since there are so many possibilities for costimulatory domain designs, it's difficult to test them all in the lab.Based on his experience in the Church Lab, Dan has developed tools to “multiplex” biological experiments; that is, to test multiple biological hypotheses in the same experiment and increase the screening power.Dan and his co-author Camillia Azimi developed “CAR Pooling”, a multiplexed approach to test many CAR designs at once.Using CAR Pooling, Dan tested 40 CARs with different costimulatory domains in pooled assays and identified several novel cosignaling domains from the TNF receptor family that enhance persistence or cytotoxicity over FDA-approved CARs.To characterize the different CARs, Dan also used RNA-sequencing.ImpactThe CAR Pooling approach may enable new, potent CAR-T therapies that can change the game for solid tumors and other cancers that are currently tough to treat.Highly multiplexed approaches like CAR Pooling will allow us to build highly complex, programmable systems and design the future of cell engineering beyond CAR-T.In addition to new therapeutics, high-throughput studies will allow us to understand the “design rules” of synthetic receptors and improve our understanding of basic immunology.Paper: Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies
Most oncology drugs turn things off—Alligator Bioscience prefers to turn things on, specifically, the immune system, by way of stimulation with CD40 and 4-1BB agonists. In this podcast, Alligator CEO, Søren Bregenholt, discusses the latest clinical data for lead anti-CD40 asset, mitazalimab, as well as two distinct 4-1BB agonists in development. Additionally, he answers the critical question: How did you tame the toxicity of these signaling molecules when so many others have failed?
Andrew Gluck is General Partner of irrvrntVC, a firm focused on early-stage companies in the DTC, AdTech, and NextGen Commerce areas. He especially loves partnering with first-time founders so they can learn from the mistakes he made as a founder. Prior to that he co-founded and ran Agency Within, the fastest-growing independent DMA with a focus on direct-response, data-driven marketing. He managed close to $1BB in spend for clients like Nike, Billie, Zola, Outdoor Voices, Goop, and Etsy. In this episode, we cover: - How he started investing? - Building the biggest digital marketing agency in the United States. - Raising a 10MM early-stage fund - What he looks for in a company before investing - Where does majority of his deal flow come from? - How he stands aparts from other investors? - Change in investing strategy owing to the recent slowdown and much more.. Links: Website: https://www.irrvrnt.com/ Pitch: http://irrvrnt.com/#pitch Twitter: https://twitter.com/irrvrntVC Portfolio companies mentioned in the episode: RevenueRoll - http://revenueroll.com/ Carawayhome - http://carawayhome.com/ Hosted by: Prashant Choubey Website: https://choubeysahab.com/ Twitter: https://twitter.com/ChoubeySahab Instagram: https://www.instagram.com/choubey.sahab/ Youtube: https://youtube.com/ChoubeySahab Linkedin: https://www.linkedin.com/in/choubeysahab Email: prashantchoubey3@gmail.com Full episode blog- https://vc10x.com/irrvrntvc-andrew-gluck Subscribe for more amazing episodes!
Hear how Jay Mei, MD, PhD, went from his benchtop years at the NIH to a blockbuster launch at Celgene (think, Revlimid, after stints at Novartis and J&J along the way) – to spearhead the multi-asset juggernaut that is the oncology company, Antengene. From it's “license and build” beginnings, to the advent of in-house programs (15 assets in all) Antengene is poised to hit multiple oncology targets, from a small molecule ERK 1/2 inhibitor, to a bispecific for PD-L1/ 4-1BB. And did I mention they have a global license, and are expanding indications for XPOVIO? Give a listen…
In this episode of The Vitalize Podcast, Justin Gordon (@justingordon212) talks with Andrew Gluck (@irrvrntVC) the GP of irrvrntVC, a firm focused on early-stage companies in the DTC, AdTech, and NextGen Commerce areas. He especially loves partnering with first-time founders so they can learn from his mistakes. Prior to that he co-founded and ran Agency Within, the largest independent digital marketing agency with a focus on direct-response, data-driven marketing. He managed close to $1BB in spend for clients like Nike, Billie and Zola.Andrew's Twitter: https://twitter.com/irrvrntVC Topics Discussed - How Andrew got into investing and invested in Caraway pre-product and pre-launch, Branch Furniture after reaching out on LinkedIn, and Lunchbox as the first check- Finding great founders in great markets- What makes founders stand out- The benefit of having the experience of working with a lot of different early-stage founding teams- Why Andrew over indexes on go-to-market and CAC and the level of detail founders can go into- The importance of timing at pre-seed- How hands-on Andrew is as an investor- How to find companies really early and the cap Andrew put on companies he can invest in out of his fund- The opportunity at the early stages of investing- Why Andrew started a rolling fund vs. just continuing angel investing- Figuring out the structure for a rolling fund and the amount to raiseMore about the show:The Vitalize Podcast, a show by Vitalize Venture Capital (a seed-stage venture capital firm and pre-seed 300+ member angel community open to everyone), dives deep into the world of startup investing and the future of work.Hosted by Justin Gordon, the Director of Marketing at Vitalize Venture Capital, The Vitalize Podcast includes two main series. The Angel Investing series features interviews with a variety of angel investors and VCs around the world. The goal? To help develop the next generation of amazing investors. The Future of Work series takes a look at the founders and investors shaping the new world of work, including insights from our team here at Vitalize Venture Capital. More about us:Vitalize Venture Capital was formed in 2017 as a $16M seed-stage venture fund and now includes both a fund as well as an angel investing community investing in the future of work. Vitalize has offices in Chicago, San Francisco, and Los Angeles.The Vitalize Team:Gale - https://twitter.com/galeforceVCCaroline - https://twitter.com/carolinecasson_Justin - https://twitter.com/justingordon212Vitalize Angels, our angel investing community open to everyone:https://vitalize.vc/vitalizeangels/
Summary: Rivian shares soar on debut; venomous sharks in the Thames; Musk sells over $1BB in Tesla shares.
In part one of this two-part ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of recently approved therapies for diffuse large B-cell lymphoma through examination of challenging patient cases. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 10/20/21 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] SONALI SMITH: Hello, and welcome to this episode of the ASCO Education Podcast highlighting new therapies for lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical investigation in lymphoma. I'm also the Elwood V. Jensen Professor and chief of the hematology/oncology section at the University of Chicago, and very excited to be joined by my colleague, Dr. Paolo Strati. PAOLO STRATI: Good morning to everybody. My name is Paolo Strati. I'm a hematologist and medical oncologist and an assistant professor in the Department of Lymphoma/Myeloma, and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center, Houston, Texas. And I'm also the clinical director for the Lymphma Tissue Bank. In part one of this podcast episode, we will discuss the adoption of recently approved therapies for diffuse large B-cell lymphoma, such as selinexor, tafasitamab, Liso-Cel, and Lonca-T. These therapies have transformed care for patients with this disease. And we'll start our conversation today with a patient case. SONALI SMITH: Great. Well, I'll go ahead and present a patient to you, Paulo. So this is a 78-year-old man with diffuse large B-cell lymphoma that is the germinal center-derived subtype. It is not double expressor, it is not double-hit. He has advanced stage disease with a high IPI, as well as the high CNS IPI. Luckily, his performance status is zero and he has no significant comorbidities or other health conditions. He received frontline dose-adjusted EPOC-R with intrathecal methotrexate for six cycles. But at the end, he had a partial remission. So how do you select your salvage therapy in this situation? Are you concerned about using agents targeting CD19 in the second line, given the potential need to use anti-CD19 cellular therapy, or CAR-T in the third line? PAOLO STRATI: This is a very interesting and unfortunately not uncommon case. And thank you, Sonali, for asking these very important questions. Technically, a platinum-based regimen followed by autologous transplant will be a standard answer and may be feasible. Because as you mentioned, this patient has a good performance status and non-meaningful comorbid health conditions. However, patients who are refractory to a frontline anthracycline-based regimen, such as in this case, with achievement only of partial remission at the end of frontline dose-adjusted EPOC, can potentially experience a suboptimal outcome following the standard approach with a platinum-based second line regimen. And as such, alternative strategies may be needed. To this regard, the combination of tafasitamab that, as you know, is a monoclonal antibody targeting CD19, and lenalidomide, an oral immunomodulatory agent, a combination which is currently approved by the FDA in the United States as a standard second line option for transplant ineligible patients, would be a great option in this case. Data from the three year follow-up of the phase II study that has brought to the FDA approval this combination, the L-MIND had been recently presented and have showed the complete remission rate of 40% and immediate duration of response of 44 months, including patients who received this regimen as a third line or beyond. So there is, of course, a biological concern by targeting CD19 in second line. These may potentially impact a third line use of an autologous anti-CD19 CAR-T, because CD19 downregulation may potentially be a mechanism of escape to tafasitamab. And recent data has shown the CD19 levels are strongly associated with the efficacy of CAR-T cell therapy in patients with large B-cell lymphoma. Small retrospective studies have shown that autologous anti-CD19 CAR-T can be safely and effectively used after antibodies or antibody drug conjugate targeting CD19. But we need a significantly larger and prospective data, including serial tissue biopsy in these patients before considering this combination as a standard practice in patients for whom we plan to use CAR-T as a third line. Until then, I would be cautious in using second line tafasitamab in patients, again, for whom there is a potential plan for anti-CD19 autologous CAR-T in third line. And if necessary, limited to very selective cases. Finally, recent press releases have anticipated the two autologous anti-CD19 CAR-T products, Axi-Cel and Liso-Cel, are superior to autologous settings transplanted in second line. And so in the near future, CAR-T cell therapy may become a standard second line option. And that would be an ideal option in primary chemorefractory patients as the case that you presented here. SONALI SMITH: Yeah, I agree. There are a tremendous number of options. And having anti-CD19 products as well as autologous stem cell transplant, the sequencing will be an evolution. So going back to this patient, he received tafasitamab and lenalidomide for two cycles with no significant toxicity, but unfortunately, he had further progression after two cycles based on a PET/CT scan. So what are your next steps? Would you move directly to an autologous anti-CD19 CAR-T cell therapy now? Would you re-biopsy before that? And how would you select among the three available CAR-T products? PAOLO STRATI: These are not easy questions, particularly the selection of one out of three available CAR-T products. As you said, there are currently three autologous anti-CD19 CAR-T products approved by the FDA in the United States for the treatment of large B-cell lymphoma in third line or beyond. And these are Axi-Cel, Tisa-Cel, and Liso-Cel. For all of them, the best outcome is observed for patients who have a low turmor burden at time of CAR-T infusion. And they need to either select patients with no bulky disease or to decrease it through bridging therapy. And as we define bridging therapy given between leukapharesis and CAR-T infusion. Unfortunately, there is currently no standard bridging therapy and all FDA products approved in third line can potentially be used in this specific scenario that you described, including polatuzumab with bendamustine/rituximab, selinexor, and Lonca-T, of course, beyond tafasitamab and len that has already been used in this case. Of course, when selecting a bridging therapy, there are many disease-related and patient-related factors to take into consideration, including the need to preserve the host immune microenvironment that we all know is crucial for the subsequent activity of CAR-T cells. And also, we need to give into consideration the need to preserve as much as possible, as we discussed previously, in CD19 expression. To this regard, and going back to one of your questions, I strongly recommend to re-biopsy patients if any bridging therapy is used between bridging therapy and CAR-T infusion in order to document CD19 expression before CAR-T infusion. When it comes to CAR-T product selection, as I said, it's a really difficult decision to do. And we don't have at this time randomized trials in third line. And as such, the decision is really left to the treating physician based on multiple factors. But all of the limitations of inter-study comparison, efficacy seems to be pretty much the same for the two products, maybe slightly higher based on the recent second line data. But Axi-Cel and Liso-Cel as compared to Tisa-Cel, and also as suggested by recent press release. However, due to the fact that Liso-Cel and Tisa-Cel have less potent co-stimulatory domain for 1BB instead of CD28, the rate of CRS and ICANS, the two main toxicities associated with CAR-T cell therapy, is usually lower with this to the point that some centers are able to infuse them in the outpatient setting, whereas Axi-Cel is almost always infused in the inpatient setting so the toxicity can be monitored more closely. So with older patients or those who have comorbid health condition, Tisa-Cel and Liso-Cel may be a safer option, though there's a lot of research going on trying to mitigate toxicities associated with Axi-Cel. Finally, it's important to keep in mind manufacturing time. Axi-Cel is manufactured in an average of 17 days, whereas Tisa-Cel and Liso-Cel take typically longer than three to four weeks. This can be itself a determining factor, particularly for patients who are quickly progressing and where immediate treatment is needed. SONALI SMITH: Yeah, I agree. I think there are going to be many patient product and disease-based factors that will impact both the effectiveness as well as the toxicity. And you did a really great job of explaining the role of the co-stimulatory domain potentially in some of that, as well as all of the products that are out there. It's definitely a complicated area. Going back to our patient, so he did undergo leukapharesis for Liso-Cel and received third line polatuzumab and rituximab without bendamustine. The restaging PET/CT after two cycles showed a PR with a significant decrease in tumor burden, and repeated biopsy showed high expression of CD19 by flow cytometry. He then proceeded with Liso-Cel, which was relatively well tolerated. There was only grade 1 cytokine release syndrome and no ICANS, so no neurotoxicity. And his day 30 PET/CT showed a complete remission. Unfortunately, the 90 day PET/CT showed progression. So Dr. Strati what is the outcome for patients who relapse after CAR-T? Do you recommend to re-biopsy? And what are the efficacy data for FDA approved agents for these patients? And I know this is a long question, but is there any role for repeated CAR-T or allogeneic transplant now? PAOLO STRATI: Unfortunately, currently, the outcome of patients with large B-cell lymphoma relapse or progress after autologous anti-CD19 CAR-T is suboptimal, with a life expectancy, unfortunately, shorter than six months. Hence, the need to be creative and customize treatment based on biological data. To this regard, I think it's crucial to repeat a tissue biopsy to guide subsequent therapy. As mentioned previously, there are currently four products approved by the FDA for patients with large B-cell lymphoma in third line and beyond. Two of these target CD19, tafasitamab plus lenalidomide and Lonca-T One targets CD79B, polatuzumab combined with bendamustine and rituximab. And one is an SPO1 inhibitor, selinexor. While we have no data for selinexor in patients who relapse or progress after CAR-T cell therapy, limited prospective data showed that a progression-free survival in the order of weeks is usually observed for patients who receive polatuzumab with or without bendamustine and rituximab after CAR-T cell therapy. So I would not recommend that. However, there's some interesting activity in the post-CAR-T setting for Lonca-T and for tafasitamab/len is limited to patients who still express CD19 in time of relapse. And of course, it needs to be largely and prospectively further investigated before becoming a standard approach for patients who relapse or progress after CAR-T cell therapy. When it comes to cellular therapy, repeated anti-CD19 CAR-T infusion is not shown to be successful in the original registration studies. So it is not currently something that I would recommend and is not definitely a common practice. And very limited retrospective studies have shown the use of allogeneic stem cell transplants in the post-CAR-T setting may be associated with quite elevated treatment-related mortality. So I don't suggest this as a standard practice in large B-cell lymphoma at this time. This is different from B acute lymphoblastic leukemia, where instead, allogeneic stem cell transplant is becoming progressively a standard approach. And we definitely need more data before using this consistently. While we strive to identify the optimal cell batch therapy for large B-cell lymphoma patients who relapse or progress after CAR-T cell therapy. I think the priority should be given to clinical trials, including CAR-T targeting molecules other than CD19, such as CD20, CD22, CD79B, allogeneic CAR-T there are immediately available, so without the need to wait for manufacturing times. And K-CAR, that may be less toxic than CAR-T and other non-cellular therapy biological agents. So definitely, clinical trials are, at this time, the best approach in patients who relapse after CAR-T cell therapy, as the case that you described. SONALI SMITH: Thank you Dr. Strati. As an update, this patient had repeated biopsy showing a CD19 positive relapse. He consented for a clinical trial with a novel NK-CAR targeting CD19, achieving CR which is still ongoing at nine months. And this case really does represent some of the most exciting advances that we've had for this disease for patients who can tolerate aggressive therapies and have access to clinical trials. PAOLO STRATI: Dr. Smith, I'd like to hear your opinion about another patient with diffuse large B-cell lymphoma. This patient is an 81-year-old man with a history of coronary artery disease and well-controlled diabetes mellitus, who noticed a right cervical lymph node while shaving that seemed to have popped up. He was evaluated by his primary care physician and given a course of antimicrobials. 10 days later, the lymphoma seems to be enlarging and he is referred to ENT pharyngeal biopsy. The specimen is small but shows follicular lymphoma in a portion of the sample. However, there is also concern for larger cells and possible transformation. The patient is also beginning to note night sweats and a decreased appetite. And labs are notable for elevated LDH, 500, and thrombocytopenia with a platelet count of 110. So Dr. Smith, in your opinion, is this specimen sufficient to start treatment? Or should treatment be delayed to get a larger and maybe excisional biopsy? SONALI SMITH: Yeah, thank you for this question. I think this is a challenge we have in the clinic all the time, which is what is a sufficient biopsy specimen to make a diagnosis that allows us to subtype lymphoma? As we know, every lymphoma subtype, the treatment is really guided by the histology and not so much the stage or some other factors. So having a needle biopsy is unfortunately often insufficient. In this case, we have a very strong concern for a possible transformation. And as we know, both follicular lymphoma and diffuse large B-cell lymphoma can mark very similarly when it comes to immunophenotype. Certainly, the germinal center type of diffuse large B-cell lymphoma or any transformed follicular lymphoma will be CD20 positive, CD10 positive, and it really requires architecture to be able to tell whether or not there are sheets of large cells. So the ideal outcome for this patient would be to have a biopsy that is done promptly that allows us not only to confirm whether or not there is histologic evidence of transformation, but also to conduct FISH studies to determine if there's acquisition of a MYC rearrangement. At its core, all follicular lymphoma patients essentially have a transformation of 14;18, leading to BCL2 rearrangement and BCL2 overexpression. During the transformation process, there can be an acquisition of a MYC rearrangement, which would then make this a double-hit lymphoma and certainly has a much worse prognosis and may also prompt a change in treatment if the patient can tolerate more intensive therapy. So my recommendation would be to have a biopsy. Now one other aspect is that sometimes, we don't really have the time to proceed with a biopsy, or the lymph node may be in an inaccessible area. And in that case, there are some other criteria that we can use to assume that somebody has a transformation. Symptoms such as profound B symptoms and elevated LDH, and sometimes, a PET scan with multiple areas of very high avidity, can lead you to feel or suggest that this person has a transformation. There is some controversy over the use of PET and we know it does not confirm a diagnosis of transformation. But in my opinion, this is very suggestive if there are many areas of high SUV. PAOLO STRATI: Thank you, Dr. Smith. I agree completely about the importance, when time allows, to perform either a larger core biopsy or an excisional biopsy, because as you very well-outlined, this has not just a mere diagnostic purpose, but can meaningfully affect treatment planning for patients. And actually, in this case, as you suggested, the patient eventually had multiple core biopsy that showed transformed follicular lymphoma with very evident areas of diffuse large B-cell lymphoma. FISH, as expected for follicular lymphoma, was positive for translocation for TN18, but luckily negative for MYC rearrangement. So fortunately, we didn't have to deal with a double-hit lymphoma. The remainder of his staging showed he had diffuse lymphadenopathy. And PET scan, as you mentioned, has a controversial role in the diagnosis of transformation. So there's some areas that had high avidity with an uptake with an SUV of 1215, whereas other areas were less intense with SUV 618. And usually, heterogeneity in SUV actually helps further supporting diagnosis or transformation. While meta-maps showed follicular lymphoma, no large cells. So movement was isolated in the B-cell lymphoma. So Dr. Smith, at this point, based on the provided information, what's your treatment approach in this older patient and also a patient with comorbid health conditions, but with diffuse large B-cell lymphoma? SONALI SMITH: Yes. The goal of treating any aggressive lymphoma is to obtain remission, and if the remission lasts, to hopefully offer cure to the patient. And when somebody has a transformed lymphoma, of course, there is a dual concern, which is that the aggressive component can potentially be put into remission in a durable way achieving cure. But the indolent component will always need to be monitored, although hopefully, will not be life threatening the way the aggressive component can be. Treating an octogenarian is really challenging, particularly due to comorbidities in this age group and the potential toxicity of chemotherapy. So the standard of care for diffuse large B-cell lymphoma is anthracycline-based chemotherapy. But this, of course, can have significant toxicity in older patients. And in addition, the vincristine can aggravate neuropathy. And I've personally found that the high dose steroids that are part of CHOP can also cause toxicity in older patients and patients who are frail. So unfortunately, the literature is somewhat sparse. But we do have several data sets that can guide management in this particular patient situation. The French published, over a decade ago, the development of R mini CHOP, that includes an attenuated dose of cyclophosphamide, doxorubicin, and vincristine, and leads to some durable remissions and cure. Unfortunately, the long-term overall survival is less than 50% with R mini CHOP. And so although this is an appropriate backbone, there's certainly a lot of room for improvement. And there's also toxicity even with R mini CHOP. So in their initial phase II trial, there was actual deaths related to the R mini CHOP, particularly in the first cycle or two, really necessitating some type of pre-phase help ease patients into the chemotherapy. One of the challenges that we face in the clinic is that when we meet an older patient, we both want to maximize our chance for cure, but also minimize the toxicity that is particularly pronounced. And there is very little data in terms of how to guide this at the bedside. I'm excited that SWOG, with the US Intergroup, is conducting a trial, S1918, which prospectively includes a frailty assessment tool that was developed by the Italian group in lymphoma, and then also includes serial comprehensive geriatric assessment so that we can get a better idea about quality of life both during and after treatment. So there is no great standard of care right now, but I would say that R mini CHOP, outside of a trial, is a very reasonable way to proceed. PAOLO STRATI: Dr. Smith, thank you for outlining so well what we can do to minimize toxicity and to better select patients for this type of treatment. And as an Italian practitioner in the United States, I am very excited that the Italian frailty tool will be used in this SWOG trial. Are there any other ways to further improve safety when we use chemo immunotherapy in older patients or patients with comorbid health conditions? In particular, there is a lot of concern about potentially infectious complications in these patients. And so I'm wondering if there's any routine antimicrobial prophylaxis that you recommend. SONALI SMITH: Yes. I think it's really important to maximize supportive care for our older patients with aggressive lymphomas getting intensive therapy. I did mention the pre-phase, and I would just like to mention that one more time because I do think there's data that providing a brief pre-phase can minimize toxicity with the first cycle. And how this pre-phase is given is highly variable. Again, the data is somewhat limited, but it typically includes steroids given for five to seven days with or without a dose of vincristine. And steroids themselves can have toxicity. And the dose of the steroids, I think, is somewhat controversial. In my personal practice, I use somewhere between 40 to 60 milligrams per day for five to seven days. And I do not typically use vincristine, although a prospective French trial recently did and showed that this significantly improved toxicity. Other complications that can occur really are related to infection. And so, of course, all patients should have growth factor support as per ASCO guidelines. But I also routinely give VZV prophylaxis with acyclovir or valacyclovir. And for the first cycle in particular, I have patients come back to clinic after the first dose one week later to ensure that the counts are stable and that they are doing well. This is really where our team of nurses and other providers who are part of the care team are so important and communication is also very important. PAOLO STRATI: So Dr. Smith, as you suggested, also, this patient actually received mini R-CHOP without any complications. And end-of-treatment PET/CT can showed a VL score of 3, so a complete metabolic remission, potentially. How do you interpret these findings? SONALI SMITH: So response criteria in clinical trials, and then of course, extrapolated to the clinic, have evolved in lymphoma. And the Deauville or the International Prognostic Scoring System that has been used typically defines a uptake relative to liver and mediastinal blood pool. And those patients who have a Deauville 1 to 2, which is less than that bar, is considered negative. And 4 to 5 is positive, with five being the emergence of new sites of adenopathy. The interpretation of a Deauville 3 can be somewhat more complicated, but this really outlines the limitations of just using the SUV or the PET scan uptake to measure response. For my patient and for this patient, the lymph nodes all substantially decreased in size. And having some type of combined interpretation of the uptake, as well as the size that has decreased, I think is going to be a very important part of how we approach patients going forward. So for this patient, I opted for close observation after the completion of therapy and felt that his Deauville 3, along with the decrease in the size of the lymph nodes, was very significant. PAOLO STRATI: I completely agree with that. Where PET scan is an extremely helpful tool, particularly for the management of aggressive B-cell lymphoma, can also become a major challenge when it comes to its interpretation for these borderline scenarios. And as you said, it's very important to add into the equation multiple parameters, including CT findings and overall patient performance status symptoms. So that's all we have for today. Thank you, Dr. Smith. This was a great conversation. We have learned and discussed a lot about diffuse large B-cell lymphoma, including novel biological agents, CAR-T cell therapy, management of elderly patients, and patients with comorbid health conditions and interpretation of PET/CT scan. I think this will be very helpful. And the conversation will continue beyond this podcast. In part 2 of this episode, airing in November, we will discuss new therapies for mantle cell lymphoma and for follicular lymphoma. Thank you so much to all the listeners tuning into this episode of the ASCO Educational Podcast. SONALI SMITH: Thank you. It's been a pleasure to speak with you today. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO e-learning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.
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In this episode, we hear from Jason Luke, MD, FACP, a medical oncologist and director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center. His clinical focus is on immunotherapy for advanced solid tumors as well as cutaneous malignancies and melanoma. Dr. Luke discusses a range of issues in immunotherapy, including clinical trials, toxicities, and next-generation therapies that will likely shape the future of the field. Welcome to the ASCO Daily News podcast. I'm Geraldine Carol, a reporter for the ASCO Daily News. Joining me today is Dr. Jason Luke, associate professor and Director of the Cancer Therapeutic Center at UPMC Hillman Cancer Center. Dr. Luke's clinical focus is on immunotherapy for advanced solid tumors, as well as cutaneous malignancies and melanoma. He joins me to discuss a range of issues in cancer immunotherapy. Dr. Luke, it's great to have you back on the podcast, and before we begin, do you have any disclosures to report that are relevant to our discussion today? Well, thanks for the invitation to speak today, Geraldine. I would note that I work broadly in the field of cancer immunotherapy and drug development, which means that I have interactions with all levels of pharma. So certainly I do have conflicts of interest in terms of consulting agreements or advisory roles with many of the drug companies that are developing new agents. So I would certainly suggest that anyone who's interested knows definitely follow them up. Thank you, Dr. Luke. Well, I'd like to start with a question about COVID-19, which has radically altered care for many patients with cancer. How has it impacted your patients and the critical research you're doing to advance the next generation of therapies? Well, thanks for that question. I think that's a very important one to think about in this current time. You know, firstly, for how we've done in western Pennsylvania and the Pittsburgh area, we really missed the first wave. And I think people were kind of on their high horse a little bit about how we had done such a good job. And, unfortunately, you know, as things kind of ricocheted around the country, eventually it did catch up here. Now, I'll say that we've been fortunate to not be nearly as impacted as some other areas, but just like everyone else, we've seen a major decrease in our volumes coming through the clinics, and then a slowdown in clinical trials. Now, that being said, we have now mostly returned back to full capacity. And I would sort of use that as a bridge, then, to go into thinking about how has COVID-19 impacted our patients getting immunotherapy treatments, and the clinical trials, on the other side, that want to advance the next generation of therapies. So obviously, for individual patients, this experience with COVID-19 has just radically altered their treatment. And, you know, I think everyone knows how difficult this has been for patients coming in and having to be treated without their family members. You know, earlier on in the pandemic, potentially, having to make treatment decisions kind of on their own in the room, and/or face difficult news without the amount of support we would normally want them to have. That's improved more recently, I think, with all the testing. I think like many places, UPMC tests people-- at least, you know, temperature checks them before they come in and gives them a survey. We're not testing everybody immediately that's come into the clinic, but, you know, trying to screen out anyone who's high risk. So I think that part of it has really impacted individual people, and that's translated, then, into the research space. Where earlier on in the pandemic I think there was a big movement to try to limit the number of patients coming through the cancer center just given the uncertainty, and the initial clinical trials that that impacted a lot, I think, were some of the adjuvant, or post surgical, clinical trials. So in the field of melanoma, we have two stage two, or adjuvant trials, meaning after surgery trials. And I think it was hard to justify bringing people in to start those therapies for a treatment that we normally wouldn't give. So those were therapies that were exploring a new space in medical oncology in the stage two post surgical setting. But I think that's now lightened up a little bit as people have learned how to be safer. And think we've been doing a pretty good job at our cancer center, and I think most places have, to try to avoid high risk. So that's sort of gone down and then come back up. On the earlier slide clinical trials, we never really slowed down a lot for phase one clinical trials. And I felt very much that it was the case that we needed to continue to push forward for novel treatment options for our patients because for someone who's facing advanced disease, who's progressed through standard therapies, you know, they were sort of faced with, well, do I not go in because of COVID, and knowing that that means can't get on a clinical trial. Or do I take that risk as sort of an added element to the uncertainty of a clinical trial? And so in that regard, we've continued to push forward. We've been very fortunate that we haven't had any patients yet on our clinical trials test positive for SARS-CoV-2. I know that has happened in some other places, and it's probably just a matter of time, but I think, like all other areas of medicine, we're starting to come to grips with that fact that we're going to be dealing with this for a long time. Can you tell us about the cancer immunotherapy trials that you're excited about these days? And do you think that the use of telemedicine that was adopted during the pandemic will continue to play a role in some aspects of clinical trials in the future? So there's a lot that's going on that's very exciting in immunotherapy, specifically, for cancer. And this question about telemedicine is a very important one, and I'll come back to it a little bit later. When I think about immunotherapy clinical trials, I might think about them in a couple of different ways. One would be trials that are sort of at the tip of the spear, meaning closest to clinical practice. And there, I'm really thinking about combination regiments that build on the standard of care, or explore immunotherapy in sort of new settings, but that aren't very far from the standard of care. So for example, you know, people are all aware of giving chemotherapy with immunotherapy in lung cancer, and a number of clinical trials have started to read out with similar concepts, building on standard of care with immunotherapy across a number of diseases. So I continue to find those to be particularly of interest. And further to that, I would note that some of the post surgical, or even presurgical, immunotherapy clinical trials are really starting to look exciting. So for example, in melanoma cancer, there's a lot of evidence now from early clinical trials in the neoadjuvant, or presurgical setting, to state that for patients who have a major pathologic response prior to surgery to immunotherapy that those people-- we don't want to call them cured because we don't feel quite that certain, but essentially none of them have recurred after surgery. And those clinical trials are really, really exciting. And I mentioned melanoma, but these kinds of clinical trials are now coming into investigation across a number of different diseases, so lung cancer and bladder cancer and kidney cancer. And I think we're going to see, as we move into the future, that immunotherapy clinical trials are really going to be expanding the use of these systemic therapies much more broadly than we previously had used chemotherapy. So that's one part of immunotherapy clinical trials that I think is really exciting that likely will impact on the standard of care over the next couple of years. And mostly that immunotherapy is going to be PD-1 or PD-L1 based immunotherapy. The other side of the excitement in immunotherapy, obviously, is the great unknown, meaning what kind of novel therapeutics, or new treatment options, could be developed to bring forward for our patients? You know, here we have to have some modesty to realize that, well, immunotherapy has been a very exciting, even maybe game changer, as some might state, for the field of oncology. The vast majority of patients, and for the big diseases, they don't really benefit from immunotherapy. So think colon cancer, think breast cancer, and prostate cancer. And yet, we're seeing that there are a number of exciting things going on that might be able to expand this. So one of the areas more recently has been the combination of PD-1 antibodies, or PD-L1 antibodies, with VEGF TKIs has looked exciting in a number of these different diseases. But for me, personally, who's really interested in novel therapeutics, I think it's really trying to either integrate new biomarkers, or come up with new immunotherapy, say engineering approaches, to think about expanding the benefit. So for example, we saw at the ASCO meeting this year a study of a PD-L1 antibody with an anti-TIGIT antibody in the PD-L1 high non-small cell lung cancer space. And so the biomarker here was the PD-L1, and some might think, like, oh, well that's old hat. Don't we already know about PD-L1? But some might be surprised to know that we really haven't been optimally using that in our clinical trials so far, and that's only one marker. So say we start to integrate other markers like tumor mutational burden, or even novel markers like LAG-3 status for LAG-3 trials, or myeloid signatures for myeloid-directed, or the adenosine pathway, and these kinds of approaches. If we started to stratify patients more for these clinical trials, we might find that some of the other novel therapeutics look exciting in subpopulations of patients, honestly, very similar to how we do with targeted therapy. You know, obviously no one would think it's a reasonable idea to use an end track fusion inhibitor if there's no end track fusion, and yet in immunotherapy we've kind of been doing that for a while. And then the other place that I would note is there are a number of approaches now trying to overcome some of the earlier generations of immunotherapy-- their problems-- by sort of reengineering them. And so in this regard, I mean multi-specific antibodies or molecules. In other words, molecules that can block multiple angles of the immune system at once. So one of the things that I would be aware of is that the whole field of T cell agonist checkpoints- and they have names like OX40 and 4-1BB and ICOS. The first generation of these antibodies really didn't look very exciting. There's a second generation of multi-specific antibodies that's now combining those molecules with, say, PD-L1, or another molecule, and I'm very excited to see, kind of, what those kinds of data are going to look like. And similarly, trying to combine therapeutic approaches that might sort of work on the other side of the immune system. So PD-1 really blocks the effector phage, or reactivates it, and I'm very excited to see what some of these innate immune modifiers, like toll-like receptors or sting agonists and some of these molecules might do to potentiate immunotherapy in populations of patients that we really haven't benefited with immunotherapy so far. So all of these to say that I think there's still a lot going on in immunotherapy from enhancing the current benefit of PD-1 blocking antibodies and adjuvant and neoadjuvant settings, combining with standard of care-- say VEGF inhibitors or chemotherapy-- and then more novel technologies like multi-specific molecules, innate immune modifiers, and even cellular therapies that I didn't touch on which are now starting to come into clinical trials for solid tumors like TCR transduce T cells and chimeric antigen receptor T cells, and even NK cells, and I heard about macrophage cars recently, as well. So all of that is pretty exciting. Just to finish up on this point, you asked about telemedicine, and I think this is a big wild card, and I'm not sure about this. So you know, due to COVID, we were able to take a lot more flexibility in clinical trials for patients owing to the obvious danger that people might experience by coming in. And the FDA allowed for that with multiple guidances that said it was OK to do some of this remotely. It'll be very interesting to see if and when that changes back. I am really hopeful for a COVID-19 vaccine around the turn of the year, but I'm not holding my breath either, and it may very well be that the first generation isn't what we're hoping for. So I don't know whether or not we're going to be going back to normal, in air quotes, you know, anytime especially soon. So I don't know. I think telemedicine is definitely here to stay over the near-term. Over the longer term, it's probably going to be some combination of guidance from FDA, as well as potentially reimbursement from payers as to whether or not that's going to be an approach that medical centers thinks is viable to support clinical practice into the future. Well, let's talk about toxicities, which are a huge challenge for patients receiving immunotherapy treatments. Are you concerned about this, and do you think that the field is doing enough to address toxicities? So thanks for asking that question. And maybe paradoxically, I'm going to give you two answers, which is, obviously, we need to do more because even individual patients experiencing severe toxicity is a problem. And yet, I also would like to raise the concept that maybe we should be pushing the envelope a little harder as well. So let me take the first one first. You know, in standard clinical practice, the toxicity profile of immunotherapy-- these immune-related adverse events, as we've classically described them-- they can be a major challenge. And they do require having a pre-test probability in your mind about your patient, thinking that they might be experiencing one of these things. And so education with the patient and their family is just essential so that they're aware of what these things are. From experience, I had one of these today at clinic, honestly. A patient who had had a little bit of diarrhea on an immune checkpoint inhibitor, and we gave him a short course of steroids and it went right away. And we challenged him with cycle two. For reasons unclear to me, he just didn't tell me that these exact same symptoms came back, despite my asking him, and he ended up getting hospitalized. And so that emphasizes on my part that I didn't educate him and his wife enough for them to know, and we didn't stay close enough to them. So really, the major thing that I would really remind people is communication, communication. Tell the patients to let us know. Because obviously we can take care of these toxicities and we can head them off if we know about them. But when they kind of get to a tougher place, then it becomes more of a problem. So I think continuing to educate our community about these toxicities, and continuing to engage with patients and stakeholders around this is going to be really, really important. I do want to shift, though, quickly as we think about novel drug development and sort of moving the needle with immunotherapy as well, though, that I do worry a little bit that in the research space we might be too beholden to sort of our current paradigms around immunotherapy. And so two examples to this point, which is if you look at the combination of PD-1 and CTLA-4 blockade in melanoma, it's clearly the case that the patients who have more toxicity for a short term period of time have at least as good, and maybe better outcomes, than the people who don't. And for the first generation of CAR T cells, this was similar. If you didn't develop cytokine release syndrome, essentially patients didn't benefit. And so what I worry a little bit is that we're actually not trying hard enough to generate toxicity. And that might sound kind of strange to some people, but I worry that if we have not broken immune tolerance that manifests as some sort of autoimmune-like phenomenon in our patients, especially in early phase trials, that maybe we haven't adequately explored the therapeutic window that might be possible with these agents. As almost everybody listening will realize, you know, with PD-1 it's been an amazing transformational shift in our field. And yet, what's after PD-1? It's been five years now, and we kind of haven't hit that next thing. And certainly we're making lots of progress with various approaches that we've already talked about, but we haven't continued to see that transformational shift. And like I mentioned, multiple big tumor types with lots of patients don't benefit. So I wonder whether or not we should actually be pushing the envelope a little harder for some of our combination regiments to be trying to generate greater levels of immune-related adverse events. Obviously, we can always dial the dose back, but if we don't explore the dose all the way up, we never even really know whether or not the possibility was there for some drug that we think maybe wasn't effective. Do we know that we really tried it all the way through? So I think that's more of a research question, and that's something that we're trying to engage with the FDA around. What would be a safe way to do this for patients? So that we could know better whether or not we're really pushing the envelope. Because if we stop too early, I think we may not be kind of adequately giving a chance, and we might not fully benefit from the therapies that we think could be the next, kind of, anti PD-1. Well, that's a very interesting take on the issue of toxicities. Thank you for sharing that. Before we wrap up, I'd love to ask you about your vision of immunotherapy in, let's say, five years from now. What does the future hold for immunotherapy? So as a prognosticator, I mean, I think-- obviously, as somebody who drank the Kool-Aid on immunotherapy, and I'm very excited about it, I think, for all the right reasons. If we can get people's immune responses to kick in, we can help them to avoid treatments like chemotherapy and potentially morbid surgeries. So I think about immunotherapy, again, sort of short and long term. There are certain disease types where I think immunotherapy will have an increasing role that might further, sort of, get rid of some of the classic approaches that we've taken. And so for example, in melanoma. You know, it's currently the case that melanoma is sort of a-- immunotherapy to melanoma is a backbone for metastatic disease and for stage three disease. And I mentioned earlier that the neoadjuvant, presurgical studies are starting to look really good. There are also stage two clinical trials-- adjuvant clinical trials, meaning after surgery-- for melanoma that did not involve the lymph node where this treatment is starting to look really exciting as well. So if all those trials were to be positive-- and we should have those results within just a few years-- that would really only leave stage one melanoma-- the kind that is usually removed by the dermatologist-- as the kind that would need really substantial surgical approaches. And I don't think people realize how close to realization we are there. It's not to say we wouldn't do any surgery, but the days of doing these large, morbid lymph node dissections will be gone if those trials come to pass in the way that we hope that they will. And, you know, melanoma is really just kind of the most advanced immunotherapy space. Such a paradigm could come into effect for other tumor types-- bladder, kidney, et cetera, and maybe even lung cancer-- in the future as well. But moreover, in the advanced disease setting, what I really hope we see by the year 2025 is much more strict stratification of patients' tumors and the overarching-- sort of overall description of their immune status for biomarker stratification. And so we have advocated that studying the tumor is very important for PD-L1 status and interferon gene expression and tumor rotational burden-- all these things-- but there are other components of the patient's body and their immune response. And I think we're only starting to understand, but I think we can harness, in a hypothesis-driven way, to improve patients' outcomes into the future. So for example, we're learning more and more that germline polymorphisms in certain immune regulatory genes can actually impact on patients' likelihood of developing cancer and likelihood of developing an appropriate treatment response to immunotherapy. So can we profile that ahead of time and combine that with information that we know about the tumor, like PD-L1 status? Additionally, what about the fecal microbiome, or the patient's overall commensal microbiome? So a number of high profile papers have suggested that which bacteria are resident in our body might change our immune system in a way that makes us more or less likely to get cancer and respond to different treatments. And so all of these factors-- the tumor, the host genome, the microbiome components-- all of these are measurable now with next generation sequencing approaches, and it's my hope that in the future, maybe by 2025, a multi-dimensional analysis of immunotherapy biomarkers could be applied to individual patients to really try to choose for them the optimal approach that might allow them to benefit the most from harnessing their immune system against cancer. Excellent. Well, thank you Dr. Luke for sharing your incredible insights with us today on the ASCO Daily News podcast. Thank you for the opportunity to speak. And thank you to our listeners for joining us today. If you like what you're hearing on the podcast, please take a moment to rate and review us on Apple podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
In today's episode, we hear from Dr. Raghuveer Ranganathan, a clinical instructor in the Division of Hematology and Oncology at the UNC School of Medicine at Chapel Hill. His clinical focus is lymphomas and leukemias, with a specific focus on using cellular immunotherapy to treat patients with hematologic malignancies. Dr. Ranganathan discusses how the treatment landscape has changed with the introduction of CAR-T therapies and other advances in cellular immunotherapy techniques. Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carol, a reporter for the ASCO Daily News. Today I'm speaking with Dr. Raghuveer Ranganathan, a clinical instructor in the Division of Hematology and Oncology at the University of North Carolina's School of Medicine at Chapel Hill. His clinical focus is lymphomas and leukemias, with a specific emphasis in using cellular immunotherapy to treat patients with hematologic malignancies. His research on cellular immunotherapy techniques, such as optimized TCR and CAR T-cells, has been published in peer-reviewed journals, and his work has been recognized by the Lymphoma Research Foundation and the American Society of Hematology. Dr. Ranganathan reports no conflicts of interest relevant to this podcast, and full disclosures relating to all Daily News podcasts can be found on our episode pages. Dr. Ranganathan, welcome to the podcast. Dr. Raghuveer Ranganathan: Hi, Geraldine. Thank you for inviting me and having me on your podcast today. ASCO Daily News: Dr. Ranganathan, how has the treatment landscape changed with the introduction of CAR T- cell therapies for hematologic diseases? Dr. Raghuveer Ranganathan: The CAR-T therapies have really revolutionized our treatment options in general. Currently, the main pillar of front-line treatment for hematologic malignancies is chemotherapy, with radiation sometimes playing a supportive role, and surgery being a rare adjunct. Now immunotherapy, and specifically cellular immunotherapy, has formed an additional and critical option for these diseases, especially in the relapsed refractory setting. In particular, CAR T-cell therapy has provided hope in achieving long-term remissions, and maybe even a cure in patients, with these hematological cancers who are chemorefractory, or have exhausted all other treatment modalities due to the persistence of their disease. Interestingly, due to the success in multiple-relapse refractory disease, CAR T-cell therapy is being explored as an option earlier to patients with relapsed refractory disease. As stated, chemotherapy is still the front-line option for hemotological malignancies. As an example, for diffuse large B-cell lymphoma that is not a double- or triple-hit variant, the standard of care is still R-CHOP as front-line therapy. And if the patient relapses systemically, then the goal is to give salvage chemotherapy, with the hope of proceeding to an autologous stem cell transplant, if they're in CR and transplant-eligible. CAR-T is approved for a second relapsed disease and beyond in lymphomas. It's thought, though, that patients who have been exposed to high-dose chemotherapy or numerous salvage chemo regimens display less P-cell fitness overall, which subsequently reduces the cytotoxic efficacy of CAR T-cells derived from those patients' regular T-cells. As a result, there are ongoing clinical trials comparing the use of CD19 targeting CAR T-cell therapy with aggressive B-cell lymphoma in first relapsed, and comparing it prospectively against autologous hematopoietic stem cell transplants. ASCO Daily News: So what are some of the recent FDA drug approvals for CAR T-cell therapy that you are now using when treating lymphoma patients, and what you expect to see approved in 2020? Dr. Raghuveer Ranganathan: So there are two currently FDA-approved CAR-T products that are now available for commercial use. Both CAR-T products target a CD19 antigen present on B-cell derived hemotological malignancies. One of them is axicabtagene ciloleucel, otherwise known as Axi-Cel, or its trade name of YESCARTA. And it's FDA-approved for use in adult patients who have received two or more lines of therapy for relapsed refractory aggressive B-cell lymphomas, which includes diffuse large B-cell, including high-grade variants, primary mediastinal B-cell, and transform follicular lymphomas. The other CAR-T product is also CD19-targeting, named tisagenlecleucel, which we will call as Tisa-Cel, its trade name being KYMRIAH. And it has two indications as part of its approval. One is for adults with relapsed refractory diffuse large B-cell lymphoma, including high-grade variants and transport and follicular lymphomas. So in other words, the indication's very similar to Axi-Cel, except with the exclusion of primary mediastinal B-cell lymphoma. The second indication for Tisa-Cel is for use in children and young adults up to the age of 25 years with B-cell acute lymphoblastic leukemia, or B-cell ALL, that is either refractory to treatment or has relapsed twice or more. The main difference between the two CD19 CAR constructs molecularly is that Axi-Cel has a CD28 intracellular costimulatory domain, while Tisa-Cel uses a 4-1BB costimulatory domain. Axi-Cel had an initial overall response rate and a complete response rate of 82% and 58% respectively, with ongoing complete response rates of about 35% at six months in its ZUMA-1 phase 2 trial. Tisa-Cel displayed an initial overall and complete response of 53% and 40%, respectively, with ongoing Complete Response, or CR rate, at six months of 30% in its Juliet phase 2 trial in its patients. In both trials, those patients who reached and remained in CR at eight to 10 months displayed a high chance of remaining in complete remission long-term. Several patients in both trials demonstrated conversion of a partial response to a complete response as much as 15 to 18 months after Cartesian infusion, though most of these conversions happened within the first six months. It's difficult to compare the clinical trials for each of these CD19 CAR-T products with each other because each of the trials were conducted in critically different ways regarding patient selection, disease types, allowing bridging therapy or not, and different dosages of lymphodepletive chemotherapy. How these differences matter clinically is yet unknown and requires more research at this time. However, there were some interesting similarities and results between the two trials. Patients both below age 65 and above 65 did equally well. Germinal center and non-germinal center lymphomas both responded equally to both CD19 CAR-T products. Both trials include a small number of patients with CD19 negative lymphomas, and some of them responded to CAR-T therapy. Also interestingly, the early use of tocilizumab, which is an aisle 6 receptor-blocking antibody used in cases of Cytokine Release Syndrome, or CRS, did not negatively impact response outcomes, and neither did the early use of corticosteroids for CRS and/or neurotoxicity. Now, in addition to the Axi-Cel and Tisa-Cel, a third CD19-targeting CAR-T product, lisocabtagene maraleucel, or Liso-Cel cell for short, is supposedly nearing FDA approval for 2020 in relapsed refractory lymphoma. Its distinct feature, compared to the other two products, is that Liso-Cel is formulated as specified CD4, CD8 composition ratio administered at a flat dose. At the recent ASH meeting in December 2019 in Orlando, Liso-Cel showed promising response rates that were comparable to Axi-Cel and tisagenlecleucel in relatively short follow-up time. And the pure publication of the data from its clinical trials is still eagerly awaited. ASCO Daily News: Right. And what about the use of CAR-T therapy in mantle cell lymphoma? Dr. Raghuveer Ranganathan: So relapsed mantle cell lymphomas, especially with blastoid or pleomorphic morphologies, have a dismal prognosis with available salvage therapies. And this is where CAR-T can hopefully help. At the recent ASH meeting, the ZUMA-2 clinical trial with Axi-Cel in mantle cell lymphoma showed very promising response rates. An overall response rate of 93%, with 67% CR rate, was seen in 68 patients, with most of these patients having relapsed after autologous hematopoietic cell transplants. And the majority showing refractory disease to BTK inhibition, which is the standard therapy after a first relapse. The CAR-T therapy results appeared to be agnostic towards the morphology of patients' mantle cell lymphoma. Meaning those with the more aggressive blastoid or premorphic variant morphologies responded as well as those with the classical morphologies. Grade 3 or higher CRS neurotoxicity were seen in 15% and 31% of patients, respectively. And we're waiting for the official publication of these results as well to gauge its full efficacy and safety profile in this disease sub-type for lymphoma. ASCO Daily News: Let's focus on patients with multiple myeloma for a moment. How does CAR T-cell therapy differ for patients with multiple myeloma? Dr. Raghuveer Ranganathan: So multiple myeloma tumor cells rarely express CD19. So CD19 is not really regarded as a dependable target for myeloma. B-cell Maturation Antigen, or BCMA for short, is a trans-membrane protein which is expressed on multiple myeloma cells. There have been a handful of phase 1 trials looking at BCMA-targeting CAR T-cells in multiple myeloma. And the first phase I trial was out of the NCI published in 2015, looking at 12 patients who received anti-BCMA CAR at varying dose levels where they had one stringent CR and two very good partial responses, and one partial response, with response durations lasting between 16 and 30 weeks. But eventually all of the patients relapsed, unfortunately. A follow-up trial by the same group using a different anti-BCMA CAR, with a 4-1BB post-stimulatory domain, instead of the CD28 domain used in the first trial, was used in the multi-center phase I trial with 33 patients enrolled. Similar to their first trial, the new trial had varying dose levels of the anti-BCMA CAR cells as well, and had slightly higher doses given than seen in CD19 CAR trials. An overall response rate of 85% was seen, with 45% CR or stringent CR. Very good partial response and better were only seen in the higher dose levels of at least 150 million CAR-positive T-cells or higher. Four of these patients showed ongoing CR or stringent CR of 12-plus months at the time of study publication. In a subset analysis of patients whose myeloma tumor expression of BCMA was less than 50%, and comparing them to patients whose BCMA expression was greater than 50%, there was no difference in response. 16 out of 18 patients who were assessed for MRD negativity were negative at 10 to the minus 4 nucleated cells, and median progression-free survival was 11.8 months. Another phase 1 trial out of University of Pennsylvania, using a fully-humanized anti-BCMA CAR, was administered to 25 patients, either with or without lymphodepletive conditions prior to CAR-T infusion. In the cohort of 11 patients receiving both lymphodepletion and a higher CAR-T infusion dose, an overall response rate of 64% was seen. Since publication of these studies, unfortunately though, the majority of the study patients have all relapsed with disease. It is somewhat difficult to pinpoint the reason for this large amount of relapse, but it might have something to do with the nature of the BCMA antigen itself. BCMA is cleaved by an enzyme called gamma secretase and shed off of the surface of myeloma tumor cells normally. High levels of soluble BCMA circulating in the peripheral blood, incidentally, is associated with a poor clinical outcome in general. While the study showed efficacy in a myeloma tumor whose BCMA expression was less than 50%, there is very likely an expression level below which the CAR T-cells will not be effective in identifying and eliminating a tumor. And since BCMA can be cleaved off the myeloma cell surface, it's basically an escape route for the tumor cells to evade detection from the BCMA-targeting CAR. Interesting data shown at the recent ASH Conference out of the Fred Hutchinson Cancer Center showed the addition of an inhibitor of gamma secretase keeps the BCMA from being cleaved and shed off of the myeloma tumor cell surface, thereby increasing its expression levels and keeping it on the tumor cell surface. When the gamma secretase inhibitor is combined with anti-BCMA CAR-T cells in patients, it preliminarily showed promising long-standing results in a phase 1 trial with six patients. But further follow-up and additional clinical trials are necessary to validate these findings. Additionally, here at UNC Chapel Hill, we have a clinical trial open that uses CAR T-cells targeting CD138, which is another antigen also expressed on myeloma cells instead of BCMA. We're currently enrolling patients and hope to see an efficacy in myeloma, which would help advance the treatment paradigm from our studies as well. ASCO Daily News: Excellent. Well, Dr. Ranganathan, I think it's important to address the issue of toxicities. So how are the toxicities unique to CAR-T being addressed? And do you foresee a time when biomarkers will be used to predict toxicity in patients? Dr. Raghuveer Ranganathan: Sure. The two toxicities uniquely seen with CAR-T therapy are Cytokine Release Syndrome and Neurotoxicity, otherwise known as ICANS. The pathophysiology of these two toxicities is still somewhat unknown, and an area of concerted investigation currently. Cytokine Release Syndrome, or CRS, is a systemic inflammatory response produced by a superphysiologic elevation of cytokines. IL-6, in particular, seems to be a culprit. Cytokine analyses have shown a relation between higher peak levels of IL-6 and higher grades of CRS in CAR-T patients. It's characterized by a constellation of symptoms, which include fever, malaise, headaches, myalgias, and arthalgias and rigors with fever usually being the first symptom observed with CRS onset. Though it's time of onset can vary from a few hours to more than weeks post CAR-T infusion. In severe CRS, patients can have life-threatening hemodynamic instability, stemming from capillary leakage, hypoxia, coagulopathy, and organ dysfunction. Risk factors for severe CRS include high tumor burden, higher intensity of lymphodepletive chemotherapy prior to cell infusion, a higher level of administered CAR-T cell dose, and possibly also elevated inflammatory markers at baseline prior to infusion, such as abnormally high C-reactive protein and ferritin. Since high elevations of IL-6 were noted in the early CD19 CAR-T trial patients, administration of tocilizumab, a monoclonal antibody blocking the IL-6 receptor, was noted to demonstrate a rapid de-escalation of CRS symptoms. So now tocilizumab is actually a mainstay of treatment for CRS. Corticosteroids are also used in the treatment of CRS, especially if tocilizumab is not enough to curtail the symptoms. As I had already mentioned, earlier intervention with tocilizumab and/or corticosteroids did not appear to negatively impact CAR-T efficacy in clinical trials. Now, the second unique toxicity is neurotoxicity, which is now termed as Immune Cell Associated Neural Toxicity Syndrome, or ICANS for short. It can manifest as a tremor, impaired attention, difficulty writing, expressive aphasia, and confusion, but also can develop into more serious symptoms such as encephalopathy, delirium, stupor, and seizures. In rare cases, diffuse cerebral edema has developed, sometimes as a progressive crescendo, but occasionally also with very little preceding warning or clinical signs. ICANS can happen during CRS, but more commonly occurs after CRS, and can lag behind CRS by up to two weeks. Expressive aphasia is the most common characteristic symptom that develops first in patients before other symptoms, with the symptom progression taking anywhere from hours to days. Though cytokines leaking through a disruptive blood brain barrier is theorized as a possible cause of ICANS, its pathophysiology really remains largely unknown, and is a hot area of study currently. Unlike with CRS, treatment with tocilizumab does not lead to symptom benefit because tocilizumab does not cross the blood-brain barrier. So corticosteroids are really the only option for treatment of ICANS at this time. ASCO Daily News: So what's on the horizon for CAR T-cell therapies? Do you think they will be used to treat solid tumors in the future? Dr. Raghuveer Ranganathan: So far as the horizon and future directions for CAR T-cell therapies, there are already several modifications and upgrades being attempted to improve the current science and technology. One such enhancement is adding additional co-stimulatory intracellular domains to the actual CAR construct, a so-called "third generation" CAR-T. The idea is that by increasing that matter of costimulatory domains in the CAR construct, such as adding a CD28 costimulatory domain to the 4-1BB costimulatory domain that might be already present, there can perhaps be either amplification of signals within the CAR-T cells, and also harnessing of the different properties inherent to each different costimulatory domain, with augmented proliferation tumor cytotoxicity as a result. Currently, however, third-generation CAR-T constructs have yet to show better tumor cytotoxicity and better long-term remissions clinically, compared to second-generation constructs. Another enhancement is targeting two antigens simultaneously, or dual-targeting CAR0T. One of the purposes of this approach is to minimize tumor escape. Since the current second generation CAR T-cells target one cancer antigen at a time, if tumor cells were to down-regulate the expression of the targeted antigen, it would result in the tumor being able to evade recognition by the CAR T-cells. By targeting two antigens simultaneously, it's thought that the risk for tumor escape is lessened. A spinoff of dual-targeting CAR-T utilizes a sort of Boolean logic-gated approach where the CAR T-cells can be recalibrated to activate in an inducable fashion. In these logic-gated CAR T-cells, sensing of antigen 1 by a synthetic notch receptor within a modified T-cell then induces transcription and subsequent expression of a CAR receptor, which is specific for antigen number 2. Meaning that without binding of the antigen number 1 by our genetically-modified T cell, there is no expression of the CAR receptor binding to antigen number 2, which could help minimize on-target off-tumor toxicity. Another approach is called T-cells Redirected for Universal Cytokine Killing, or termed somewhat tongue-in-cheek as TRUCK T-cells, a playoff of CAR- T cells. These cells, in addition to direct tumor killing, also produce a pro-inflammatory cytokine, like IL-15 or IL-18, on coming into contact with a tumor, which helps to recruit a second wave of immune cells in a locally-restricted fashion, hopefully, to initiate a secondary attack on cancer cells, and also help enhance its own proliferation, cytotoxicity, and longevity. Now, there are unique obstacles and challenges for CAR-T and solid tumors that make it more difficult when compared to hematologic malignancies. Some of the existing challenges include overcoming the hostile tumor microenvironment, nutrient depletion, hypoxia, and inhibitory checkpoint molecule expression on solid tumors. Now, any one of these impediments would be a strong stumbling block to try and overcome, but when all of these hurdles occur together all at once, it can be very difficult to combat. In addition, on-target off-tumor toxicity is somewhat of a bigger challenge to overcome in solid tumors. And a likely cause for this is the overlapping antigen expression on epithelial tissues from which most solid tumor types originate. And also the spatial proximity and restriction of critical sites when targeting solid tumors. For example, a few years ago, a patient with metastatic colon cancer who had received CAR T-cell therapy as part of a trial died from acute respiratory distressive failure, with the cause thought to be low-levels of being expressed on lung epithelial cells. That said, I do believe CAR T can become a viable treatment modality in solid tumors with some modifications and improvements. One such method being tested in clinical trials is combining immune checkpoint therapy, such as PD-1 inhibitors, with CAR T-cells. Another possibility is to edit the native inhibitory receptor in CAR T-cells by switching out the inhibitory receptor's intracellular domain for an intercellular domain from a stimulatory receptor. For instance, we take the native PD-1 molecule from a CAR-T cell and edit or switch out the intracellular domain, and put in the intercellular domain from CD28. What you get now is a molecule which has the PD-1 receptor on the outside, but a CD28-signaling mechanism on the inside, so that the net result is actually positive for the CAR-T, which now gets added stimulus instead of inhibition. Such switch receptors are being incorporated into CAR T-cells to augment their activity and proliferation potential. And as I mentioned before, TRUCK T-cells and logic-based CAR T-cells are also other possible methods to conquering some of these obstacles posed by solid tumors. So while there's still much more investigation to be done in overcoming solid tumors, I do hope that we can make some strong headway in the near future. ASCO Daily News: Well, thank you Dr. Ranganathan for sharing your insights on CAR T-cell therapies with us today. Dr. Raghuveer Ranganathan: My pleasure. Thank you, Geraldine. ASCO Daily News: And to our listeners, thank you for tuning into the ASCO Daily News Podcast. If you're enjoying the content, please rate and review us on Apple Podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Alan, Co-Founder of Rocket Walk, discusses the meaning of "done" and how to prioritize projects with Tim Sunde, Product Owner/Analyst and Agile Coach.Tim Sunde is an award-winning, Product Owner/Analyst & Agile Coach with over 25 years of experience in rapidly delivering business transformation through technology and leading cross-functional teams, for a variety of companies with annual revenues of $1MM to $1BB across multiple industries. He has an extensive experience in identifying, designing, and delivering improvements in systems and processes. Connect with Tim:LinkedIn: Tim Sundewww.TimSunde.comDiscussion Includes:- The definition of "done"- Accurately defining projects - Minimal viable product- Prioritizing projects and tasks- The value of retrospectivesIf you'd like more information on Agile Marketing, or if you are interested in appearing as a guest on our show, please contact us at info@rocketwalk.com or visit our website, www.rocketwalk.com
Alan, Co-Founder of Rocket Walk, talks with Tim Sunde, Product Owner/Analyst and Agile Coach, about how to create a big impact within a team by making small, Agile-based changes.Tim Sunde is an award-winning, Product Owner/Analyst & Agile Coach with over 25 years of experience in rapidly delivering business transformation through technology and leading cross-functional teams, for a variety of companies with annual revenues of $1MM to $1BB across multiple industries. He has an extensive experience in identifying, designing, and delivering improvements in systems and processes. Connect with Tim:LinkedIn: Tim Sundewww.TimSunde.comDiscussion Includes:- Easy to implement items to help workflows- Shared communication and groupware platforms- Team agreements- Retrospectives: why they're necessary and why some people don't do themIf you'd like more information on Agile Marketing, or if you are interested in appearing as a guest on our show, please contact us at info@rocketwalk.com or visit our website, www.rocketwalk.com
Intro Favorite pitcher hype song (for John McMillon): Big Bad John, Jimmy Dean; not the greatest ending for ole Big Bad John, but cool nonetheless Jimmy Dean from Plainview “Best known for 1961 hit “Big Bad John”, his 1961 recitation song about a heroic miner. The song went on to become #1 on Billboard pop chart; sold over a million copies and was awarded a gold disc. Track peaked at #2 in the UK Singles Chart. Song won Dean the 1962 Grammy Award for Best Country & Western Recording” Basketball Chris Clarke transfer from Va Tech; 6’6 215lbs; rated #8 grad transfer for 2019 #62 recruit coming out of high school, lower than only Jahmius Ramsey and Khavon Moore 2017-2018 stats: 8.2 ppg, 6.3 rebounds, 98 assists, 31 steals Sat out 2018-2019 season, dismissed from Va Tech after misdemeanor drug charge (roommate also charged with misdemeanor drug possession charge, but not suspended) Career stats: 54% FG, 42.4% 3FG (low volume shooter, 14/33 in 2017-2018), 66.6% FT (draws a lot of contact, shot 94 FTs in 2017-2018, would have been 3rd highest on this year’s Tech team); 1.93 TO/g (Culver had 2.7/g this year, Mooney had 2.5), 2.6 assists/gm; 6.5 rebounds/gm (Culver led Tech with 6.4) Called a “junkyard dog defender” by Rob Dauster of NBC Sports; was Va Tech’s best defender Averaged giving up 98.7 points per 100 possessions; all of Tech’s starters averaged better, closest Tech starter would have been Moretti at 93.8 Tyreek Smith committed; 6’8 205lbs; Trinity Christian (Cedar Hill, TX) 4*, rated between 101st and 153rd overall in 2019 class Played on same high school AAU team as 5* target RJ Hampton Interior slasher, dunker, lane defender; not much of a jump shooter Still have one scholarship available for 2019-2020 (Khalid Thomas decommitted) Only 3 contributors from 2018-2019 season returning: Davide Moretti, Kyler Edwards, & Deshawn Corprew (5 total counting Kevin McCullar & Andre Savrasov) Guards: Moretti; Edwards, McCullar, Jahmius Ramsey, Clarence Nadolny Forwards Corprew, Savrasov, Terrance Shannon, TJ Holyfield, Chris Clarke, Tyreek Smith Center Russel Tchewa Football Anything? Wells was at all 3 baseball games (headsetless); man among the people, incognito; he talked to me for 2 seconds about me keeping score and said “old school. I like it”. So now, I’ve arrived. Baseball Season Awards Josh Jung, Co-Big 12 Player of the Year (49 GP, .333/.597/.471 (OPS 1.068), 186 ABs, 49 Rs, 62 hits (20 2B, 1 3B, 9 HR), 49 RBI Shared with Baylor INF Davis Wendzel (40 GP, .385/.647/.500 (OPS 1.147), 159 ABs, 39 Rs, 60 hits (17 2B, 8 HR), 39 RBI For comparison, Cam Warren; 51 GP, .354/.667/.448 (OPS 1.115) 189 ABs, 51 Rs, 67 hits (16 2B, 2 3Bs, 13 HRs) 65 RBI https://kkam.com/why-does-the-big-12-love-co-award-winners-so-much/ G avg OB% slg% AB R H 2B 3b HR RBI BB SO Wendzel 40 .385 .500 .647 156 36 60 17 0 8 39 27 32 Warren 51 .354 .448 .667 189 51 67 16 2 13 65 31 21 Jung 49 .333 .471 .597 186 49 62 20 1 9 49 46 34 All Big 12 First Team: Jung, Warren, Gabe Holt, Caleb Killian, Taylor Floyd All Big 12 Second Team: Brian Klein, Dylan Neuse, Clayton Beeter Honorable Mention: Braxton Fulford, Dane Haveman, John McMillon All Freshman Team: Beeter, Micah Dallas, Cole Stillwell Came into the weekend .5 game back from Baylor Thursday, L 1-3 in 14 Friday, W 7-2 Saturday, W 8-4 Conference champions again! Third time in 4 years, unshared this season National Seed/Super Regional Host discussion h/t KP Dinger Derby Texas Tech unshared conference champions of #2 RPI conference Texas Tech, RPI #9, SoS #12, NonCon RPI #16, NonCon SoS #17 Louisville, RPI #7, SoS #27, NonCon RPI #21, NonCon SoS #119 Arkansas, RPI #6, SoS #11, NonCon RPI #43, NonCon SoS #158 Big 12 Tournament schedule Your pod includes 1 seed Tech, 4 seed WVU, 5 seed Kansas, 8 seed Kansas State (other pod is 2 seed Baylor, 3 seed Okla St, 6 seed TCU, 7 seed Oklahoma; will only face a team from this pod in championship game) Double Elimination format Will face KSU first (Wed 1230), likely Griffin Hassall on the mound (4.25 ERA, 1.27 WHIP, 2-3 on the year on 13 appearances, 35K:24BB (1.45 K:BB ratio) Pitched vs Tech 3/30, L for Hassall, 6 IP, 4H, 3R (1ER), 2BB, 2K Likely to face WVU in second round (Thursday, 4p); or Kansas is they upset; WVU #2 pitcher is Jackson Wolf (4.75 ERA, 1.51 WHIP, 2-4 on the year with 14 appearances, 46K:26BB (1.77 K:BB ratio) Pitched vs Tech 4/13, W for Wolf, 4.1 IP, 8H, 3R (3ER), 1BB, 3K Questions Going Yard What we learned
This week, we welcome Angad Chowdhry and Anurag Banerjee, the co-founders of Quilt.ai, the company using big data to understand people better. We speak to them about AI for Social Good. Dr Angad Chowdhry completed his PhD from SOAS, the University of London. His academic specialization is anthropology and media studies. He has conducted big data / big culture research in over 70 countries across clients and industries. At Quilt.ai he is working on integrating the latest advances in cognitive computing with the exponentially increasing human data that is being openly generated to conduct anthropology at scale. For almost a decade, Anurag Banerjee ran a 800 person team for global business development at American Express. He built a fee based Travel Big Data business to $1BB before starting on his entrepreneurial journey. He was employee number one at Jana Mobile (invested in by Publicis and Verizon ventures with $100MM raised). Post exiting Jana, he raised $150MM across multiple ventures he has backed / advised. SocialCops is his venture prior to Quilt.ai was funded by Ratan Tata & work for India’s Prime Minister Modi. Discover more on our website: https://www.soascodingclub.com/soas-radio-episode-8-ai-for-social-good
This week, we welcome Angad Chowdhry and Anurag Banerjee, the co-founders of Quilt.AI, the company using big data to understand people better. We speak to them about AI for Social Good. Dr Angad Chowdhry completed his PhD from SOAS, the University of London. His academic specialization is anthropology and media studies. He has conducted big data / big culture research in over 70 countries across clients and industries. At Quilt.AI he is working on integrating the latest advances in cognitive computing with the exponentially increasing human data that is being openly generated to conduct anthropology at scale.For almost a decade, Anurag Banerjee ran a 800 person team for global business development at American Express. He built a fee based Travel Big Data business to $1BB before starting on his entrepreneurial journey. He was employee number one at Jana Mobile (invested in by Publicis and Verizon ventures with $100MM raised). Post exiting Jana, he raised $150MM across multiple ventures he has backed / advised. SocialCops is his venture prior to Quilt.ai was funded by Ratan Tata & work for India's Prime Minister Modi.Discover more about this interview on our website here.Twitter: @global_futuresInstagram: @global_futuresSubstack Hosted on Acast. See acast.com/privacy for more information.
Nick is the founder and Managing Partner of Operose Partners, an investment advisory and family services firm he started in 2017. It's off to a phenomenal start. Prior to starting Operose, Nick was a partner at Geneva Capital and helped the firm grow its assets under management from $1BB to $7BB in 3 years. He joined Henderson Global…Continue reading ➞ Nick Bauer, Billion Dollar Underdog in Asset Management – Episode 12The post Nick Bauer, Billion Dollar Underdog in Asset Management – Episode 12 first appeared on Mike Malatesta.
Nick is the founder and Managing Partner of Operose Partners, an investment advisory and family services firm he started in 2017. It’s off to a phenomenal start. Prior to starting Operose, Nick was a partner at Geneva Capital and helped the firm grow its assets under management from $1BB to $7BB in 3 years. He joined Henderson Global…Continue reading ➞ Nick Bauer, Billion Dollar Underdog in Asset Management – Episode 12
What does it take to build success? Jim Akers shares why community is the key to business success. You can not get where you want to go on your own. We were created for community. In entrepreneurship a trusted coach, mentor, and leader will help you on the journey. It's the support of each other and input that can drive us past fear, failure, and other obstacles to make our dreams real!In the episode, we also discuss pivoting your business, being an ordinary person living an extraordinary life, giving more than you take, finding unlikely sources of clarity, focusing on process, firing your friends, flourishing in life, asking for help, doing things that matter, finishing strong, and much more.Jim Akers is the Founder and President of J.D. Akers & Associates.Jim is a graduate of Washington State University, earned his M.B.A. from Pepperdine University in Organizational Behavior, and a Certificate in Advanced Management from Stanford University.Today Jim is a leader, achievement coach, author and speaker focused on helping people clarify and win at what matters most.Early in his career, Jim wrote “How to Win the Achievement Game” a self-published guide to building a successful life plan. While in the midst being newly married, completing an M.B.A., and pursuing a career he sold nearly 3,000 copies. By way of “How to Win the Achievement Game,” Jim was invited to speak to the senior leadership of Rockwell International’s Space Shuttle team on performance and achievement when he was 25 years old.After four award winning years in commission sales, Jim was named Vice President of Sales at the age of 29. Jim lead sales growth from $350MM a $500MM resulting in this privately held company to be acquired by International Paper. At International Paper, Jim quickly rose through a number of leadership roles. But when cancer prematurely took the life of a family member he set significant career advancement on the sidelines, and moved back to Southern California to support his family.Jim became one of the youngest Group Vice President’s in International Paper history leading a $1BB business with 21 locations and 1,200 employees serving customers around the globe with packaging, custom packaging design, facility supplies, and printing papers. If you have touched an iPad or iPhone you touched Jim’s team’s work.In 2013, after 25 years as a senior corporate leader Jim achieved his dream to retire by the age of 55.Jim didn’t retire but redeployed. His love for coaching, mentoring, and leadership lead him to turn his full attention to helping people clarity and win at what matters most to them.People’s thirst for encouragement led Jim to launch Impactful Notes—a free service that delivers a powerful note of inspiration and encouragement on a daily basis.Jim’s newest book, “Tape Breakers, How to Positively Impact the People You Love, The People You Lead, and the Causes that Stir Your Heart,” was released in 2016 and was a “Top New Release” on Amazon.Jim and his wife Kristi have been married for 36 years and live in Southern CaliforniaJim’s clients include The PGA of America, Dove Mortgage, International Paper, Old Castle Industries, Shaw Industries, and SouthBay SearchInterview Segments - This is where you can find each section of the interview.Intro / About Jim: 1:00 minutesInterview: 3:20 minutesRapid Rire Questions: 37:20 minutesWebsite: http://jimdakers.com/Facebook Group: https://www.facebook.com/groups/ClaritytoWin/Special Offer: Text jumblethink to 33444
Welcome to another episode of Prospects After Dark, hosted by Kyle Reis. In this episode Kyle... Covers Alex Reyes's rehab start in Peoria. 5 IP, 1H, 12Ks, 1BB, ya. Gretchen Piscotty ALS Raffle Donation Does a Miss Cleo impression Takes 100 questions involving everything from Waino's future, Tyler O'neill raking in the minos. Juan Yepez. Bud Norris closer rule when Holland gets healthy. Delvin Perez update. Continues his love for Andrew Knizner. Elehuris Montero potential all star. why Jordan Hicks isn't in any of the top 100 prospect lists. Excitement in the Minors organization is real. Watch the video, listen on Podcast (iTunes, Soundcloud #BirdsontheBlack)
Jim Akers is a former Fortune 50 senior executive turned speaker, author and coach. He helps ambitious people focus their time, talent and resources on success that leads to maximizing their impact and influence on the people they love, the teams they lead and the causes that stir their hearts. Jim is a graduate of Washington State University. He holds an M.B.A. in organizational leadership from Pepperdine University and an Advanced Management Certificate from Stanford University. Jim has won sales and achievement awards with Northwestern Mutual Life Insurance Company, Owens-Corning Fiberglas Company, Kirk Paper Company, xpedx and International Paper Company. At the age of 29, Jim was named V.P. of sales for a $500MM distribution company, the youngest group vice president in the 120 year history of International Paper Company. As group vice president at xpedx, Jim lead a $1BB distribution business with 21 locations in the Western U.S. and serving customers around the globe with packaging, custom packaging design, facility supplies, and printing papers. If you've ever touched an iPad or iPhone, you've touched work Jim’s team pioneered. Jim has authored three books: How to Win the Achievement Game; 14 Strategies for Breakthrough Performances; and most recently, Tape Breakers, Maximize Your Impact with People You Love, Teams You Lead and Causes that Stir Your Heart. Tape Breakers debuted as the #1 New Release on Amazon in March 2016 and was recognized as a 2016 Book of the Year along side the best selling new releases from Adam Grant, Ryan Holiday and Jake Knapp. Jim’s clients include The PGA of America, Old Castle, Shaw Industries, International Paper, Pearson Smith Reality, TD Realty Group along with a variety of non-profit and faith-based organizations. Jim met his wife Kristi at Washington State University. They celebrated their 12,776 day anniversary in June and have two adult sons Matthew and Andrew, who no longer require their credit card.
In episode 037, my guest Randy Davis shares with you his Bootstrapped Billionaire Project where he will go from $0 to $1BB in revenue in 7 years flat. His goal is to eliminate all excuses entrepreneurs have about starting a business from scratch. He discusses why being at rock bottom is the perfect place to be, and his approach to getting billionaire mentors. This one is a MUST listen.
Max Niederhoffer is a venture capitalist with Sunstone Capital, a $1BB fund based in Copenhagen.
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