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Sep 10, 2020

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.