John P. Leonard, MD (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. John Leonard. And today with this episode, I'm going to be passing my hosting duties over to a great colleague of mine and frequent guest on this program, Dr. Manish Shah, who will be taking over as the new host of CancerCast.

Dr. Shah is the Director of the Gastrointestinal Oncology Program and Chief of the Solid Tumor Service at Weill Cornell Medicine and New York-Presbyterian Hospital. I've worked with Dr. Shah for many years. And some of you may recognize him from our annual ASCO episode where we review top research presented at the American Society of Clinical Oncology meeting.

He is a wonderful oncologist who has great insights into different aspects of clinical and research oncology. And I'm really excited for him to step into this role as the new host of CancerCast. I also look forward to coming back to continue the Leonard List special edition episode, in a role reversal where I can be a guest.

So, it's really great to be here and mixed feelings, some sadness, but some excitement for the future. Manish, welcome and thank you again for agreeing to take on this opportunity or challenge or responsibility.

Manish Shah, MD: Thank you so much. And thank you to the program for thinking of me. I've always enjoyed our episodes together. I think that this is a great forum for discussion to happen on advances in cancer care. And really, you've led the way, I think, ahead of many people as usual. So, I really appreciate that, Dr. Leonard. And I look forward to stepping into these shoes. I won't fill them, but I'll try.

John P. Leonard, MD: Thanks for the kind words. And before we get into some areas of cancer research and where it's going and what the future holds. Some of you may be aware of this, but for those who either have forgotten or weren't aware, we started this podcast, Weill Cornell Medicine CancerCast, in 2018. And it's hard to imagine that seven years have gone by since that time. I think about many issues that have come about. We think about the progress in cancer research during that time. Obviously, everybody remembers their own personal changes and what's happened in the last several years.

And of course, we have to recognize the pandemic that's happened and the changes that happened that were associated with the horrible challenges, but in some cases, the remarkable stories that came out of what happened; and the cancer community really did some heroic things. Everybody was touched by the pandemic, but cancer patients in particular having their own experiences and challenges. So, layering that into everything that's happened in cancer care and research since that time, I think is really something that bears reflection and is important.

In 2018, and I think it's fair to say that at that point in time, podcasts were relatively new. And in fact, I had some discussions with members of our team here at Weill Cornell, where we were just kind of brainstorming on ways that we could contribute to the field of cancer and cancer education, cancer awareness, cancer information, and a podcast seemed to be an interesting way and a potentially important and impactful way to do that. That was a time when Twitter was relatively new, now X. Other social media programs were out there. And it really became clear that a podcast would be a great opportunity to share some of the great things happening in cancer research and cancer care, things that really everybody touched by cancer could benefit from. And this became really a forum to bring on different people, and share expertise. And I also, I think personally have looked at it as a way for me to learn. And I think it's been a great venue for that and hopefully many of you in the audience share that perspective.

So, I am really proud of the range of guests and topics that our team has brought forward. And really am appreciative of people that have taken the time to participate, to share their wisdom, their experiences, their insights, their ideas, and also the audience that has hopefully benefited from this program, as well as contributed some ideas.

So, I've gotten a lot out of it and I'm happy to turn over the baton to Dr. Shah, who will be wonderful in this role, and I know has great insights and ideas along with the team at Weill Cornell, to continue to bring important topics to the forefront.

So, Manish, I think this is a great time to reflect a little bit on, and you've shared this with the audience at different points in time, really how cancer research and cancer care have evolved. If we think back and as one example, you led efforts to bring forward knowledge and research and led research projects around cancer care during the pandemic. Maybe we can take a minute, since we're on that topic, have you share your thoughts and some of the learnings.

Manish Shah, MD: Well, the pandemic was really life-changing and transformative in many ways. I remember, here in New York City, the streets were empty and there was no congestion pricing. It was truly just a pandemic. And the medical center really did transform. You were part of the leadership team that helped do that. The way that we were able to navigate that was really eye-opening and inspiring as well.

So, from a cancer standpoint, one of the biggest challenges was how do we continue patients’ treatment while in the midst of being very afraid that someone could be infected. And if you have a compromised immune system, or if you are on some kind of anti-cancer therapy, some chemotherapy, would you be at higher risk of getting the infection or would your infection lead to more harm than in someone who isn't on treatment?

So, Monika Safford, who is an epidemiologist and a public health researcher here, created a database of everyone admitted to New York-Presbyterian Hospital who had the diagnosis of COVID or SARS-CoV-19. And one of the studies that we did was we looked at the patients who had cancer in that database and compared them to patients who didn't have cancer. And we were able to also look at patients who were on chemotherapy versus patients who didn't have chemotherapy. So, in the end, there was about a thousand patients were enrolled over about a year, who had cancer and about I think maybe 4,000 or 5,000 who didn't have cancer that were enrolled. So, it was a pretty large cohort.

And we were able to show that having cancer didn't actually mean that you had a worse or more severe infection. Having chemotherapy didn't mean that you had a worse or more severe infection. And that was actually informative, because we were able to feel more comfortable giving chemotherapy to patients and making sure that they were safe. So, that was one of the key studies that we did in the first six months of the pandemic, to try to ensure that we could provide cancer care to patients who needed it. And that was very, very important.

The other thing that we worked on was actually your idea. So, we were worried about the infection spreading amongst the healthcare providers. And the way that we give chemotherapy, there's a group of doctors that work on any given day. Then, there's nurses that work with the doctors and then there are nurses in the chemotherapy unit that provide the care to the patients. And one of the ideas we implemented, was we created pods on our unit.

And this pod would work on certain days. And every night, the area would be sterilized so that if there was an infection, it would be isolated to that pod. And we were able to then do that and rotate through. We did that for about six months, and we were able to continue our care. So, these were basic infection control skills that we kind of applied to the pandemic to try to ensure that people were able to get care.

And so, we actually published that methodology in the New England Journal Catalyst publication as well. The work at Cornell on COVID was actually really quite amazing. I think New York Hospital was actually the first hospital in New York area to actually have a COVID-infected patient. So, there were publications in terms of vent management, publications in terms of how to test for the virus. What were your thoughts on that?

John P. Leonard, MD: Yes. What you describe, I think, was really an incredible mobilization of resources and creativity and ideas around how could we answer problems that were immediate and staring us in the face, because patients needed to be treated and we had to come up with solutions quickly. And most of the time, I think they were good solutions and sometimes they were imperfect, but we learned from them and kind of pivoted and moved forward.

And being able to come together and rally to solve problems is something that I think would be great if we could translate to other areas.

You think about different technologies that have impacted things, whether it's new antibodies, new vaccinations, new technologies, new diagnostic skills, and tools. All of these things that were so rapidly developed during COVID are things that, in some cases, have application to cancer or have some relationship to cancer and cancer therapies that offer great promise and, hopefully, will lead to better and improved cancer treatments in the future.

Maybe now we can pivot a little bit from the pandemic, and we want to recognize still for many cancer patients and others with certain chronic illnesses, immunosuppression remains an issue even if much of the general population fortunately can be more relaxed about COVID infections. It's important to keep in mind that many patients can't be so relaxed and that continues to be an issue.

Cancer therapy and cancer care continues to evolve. And I think it would be great if we could reflect a little bit about some of the accomplishments and achievements and improvements that have happened over the last several years and where we think they're going.

So Manish, I might ask you to start with some of your thoughts and maybe you could give us a perspective on immunotherapy in solid tumors. I think that's an area that you and your colleagues have made an impact in. And certainly, across the spectrum of cancers is a cross cutting of modality of treatment that in the last seven years has revolutionized cancer treatment. And also, I think for the future offers great promise.

Manish Shah, MD: As I was reflecting on what's happened over the last seven years, this is an area that has actually completely changed oncology. And in, particular, solid tumor oncology. So, just a 30-second kind of primer on immunotherapy.

The way that cancer develops is it develops in a patient, in part, by masking itself from the immune system. So, the immune system is geared to try to get rid of pathogens, bacteria, and viruses. And when it's overactivated, it can actually attack the person's own body. So, that's how you get arthritis or Crohn's disease or something like that. There's a balance that the immune system has to have between attacking something that's foreign and not attacking something that’s self.

Cancer originates from the body, so it’s self, but it does have mutations. And so, the immune system can recognize it sometimes. But the way cancer evolves is that the cancer develops a way to protect itself from the immune system.

So, immunotherapy are drugs that actually avert this curtain that cancer cells have developed. It kind of lifts this curtain and allows the immune system to attack the cancer.

So now, we have drugs called checkpoint inhibitors. And there's two main classes that are approved. One is a checkpoint inhibitor that blocks either PD-1 or PD-L1. These are proteins on immune cells. And the other class that blocks CTLA-4. Most recently, there's a class that blocks LAG3. But these are all different names of proteins that affect how well the immune system can work. And so, by blocking these proteins, you can activate the immune system against the cancer.

And in the last seven years of the podcast, it's been so transformative that now immunotherapy is part of the standard treatment and sometimes the only treatment. So, it replaces chemotherapy in several tumors. So, there are approvals for immunotherapy in lung cancer, in colon cancer, in bladder cancer, in renal cell cancer. There are approvals in gastric and esophageal cancer. The list goes on and on. And it doesn't work equally well in everything. And in some cancers, it works better than others. But it has completely changed the way we think of treatment in terms of the ability to activate the immune system.

I think it resonates with patients as well. I describe it as a drug that allows the patient's own immune system to fight their cancer, and that is actually encouraging. And then, the most exciting thing, I think, is that when you can replace chemotherapy with immunotherapy; and that's one of the things that we might want to expand on in a future podcast is, a recent New England Journal article, where they demonstrated that you could give immunotherapy to some group of patients and you may be able to avoid even surgery. So, starting off with immunotherapy as a salvage to then combining it with chemotherapy to then replacing chemotherapy. And now perhaps, working so well that you may be able to avoid surgery. It's just remarkable how the field has changed and expanded.

And as we look to the future, the next steps are the patients that aren't benefiting from immunotherapy, why is that? Can we figure out how to do that? Can we make immunotherapy work better? Can we use it in a context where people can get this therapy and avoid other therapies like we talked about?

And then, the other thing that we should probably talk about a little bit is actually the side effects. So, by lifting this curtain and allowing immunotherapy to activate the immune system against the cancer, sometimes it overactivates, and then you end up getting really bad diarrhea or shortness of breath, or a rash or arthritis. These are things from overactivating the immune system, we could learn how to be smarter about that so we could give these therapies while minimizing toxicity. So, you're absolutely right. This is, I think, one of the most transformative things that's happened during the lifetime of this podcast.

John P. Leonard, MD:  I think another area is cellular therapy, and that dovetails very nicely into some of the areas you talked about. We have CAR T-cell therapies. These are immune cells that are removed from the body and are re-engineered to be better fighters of tumor cells. They capitalize on many of the same issues that you talked about from the standpoint of the immune system being unable to effectively kill tumor cells.

But if you can support the immune cells or re-engineer the immune cells to be better fighters against tumor cells or to not be blocked by the tumor cells in the same ways that tumor cells can evade the immune system's natural defenses, that these cellular therapies may be effective for a number of different situations. We've talked about these issues on the podcast previously, but these can be effective particularly for blood cancers, lymphoma, certain leukemias, multiple myeloma, and we're now seeing more and more of their use in solid tumors, at least in clinical trials, and some with very promising results.

We see different versions of cellular therapies being used in prostate cancer, in melanoma. There are cells that are called tumor-infiltrating lymphocytes that are immune cells that can be essentially collected from the tumor or that have some ability to react with the tumor and can be re-engineered to be even more effective. And I think that is really an area that has great promise.

Manish, I’m interested in your thoughts about the future. This has really great potential as we think about new strategies for solid tumors.

Manish Shah, MD: I agree completely. And I think another thing that's happened in the last five years that has been really, really transformative is this idea that if you're able to identify a target, and inhibit or hit that target with a treatment, you're probably better off. I think that's a concept that really is probably now much more ingrained. And it's very routine now in solid tumors to do profiling of the tumor to try to understand what targets are available.

And that segues a little bit to a new therapy that we will, I think, talk about in the future, because it's just now on the horizon. And these are inhibitors of KRAS. So, KRAS, K-R-A-S, is a protein that provides a growth signal to our normal cells. But when it's mutated, it provides a survival advantage to cancer cells. And about half of all cancers have a KRAS mutation and only recently, in the last 18 months or two years or so, have there been an ability to develop treatments that block or inhibit specific KRAS mutations. And that's also quite transformative in lung cancer. There are approvals and there are going to be approvals in other diseases as well. So, that's an exciting area, but it's in line with kind of the research advances that are happening as we understand the biology of cancers and how they work to have a survival advantage or how they work to mask itself from the immune system. All the different features that cancers are able to use to provide an advantage for the cancer cell, these are things that we can target therapeutically to try to treat the cancer better.

John P. Leonard, MD: I think one other area that I would like to touch on and highlight, as we wrap up this part of our discussion, is the issue of circulating tumor DNA. I think that is an area where we have seen dramatic changes and really important changes. All of our cells shed DNA, which as you know is the genetic code for cells. Tumor cells when they're in a person's body also shed DNA and, in some ways, shed more DNA and certain types of their DNA into the bloodstream. And those can be detected through sophisticated molecular tests. And those can be analyzed in a laboratory. And so, the concept here is that this general form of molecule released from tumor cells can potentially be used for early diagnosis. It could be used through blood tests. It could be used for characterization of a tumor so that perhaps rather than doing a biopsy of the tumor itself, you could sample the bloodstream and analyze this genetic material. You could also monitor response to treatment using blood tests that would analyze this material.

And then, you could potentially look for relapses in patients, or persistent disease in patients where perhaps you didn't otherwise have any signs of relapse or persistent disease. Instead of doing CT scans and PET scans, you could potentially sample the blood and look for these kind of genetic needles in haystacks to be able to see if the tumor was still there, or signs of the tumor was still there. And so, this sort of liquid biopsy or minimal residual disease testing, there are lots of terms based on what the scenario might be. I think these are also potentially useful across the spectrum of cancers, both in liquid tumors and in solid tumors.

And I think, while there's a lot of work to do and a lot of dots to connect around this technology, this is something that could potentially continue to evolve in its use and its value and could help patients and help doctors in designing treatment strategies or monitoring strategies or early detection strategies in very impactful ways.

So, Manish, maybe just one brief comment on your thoughts around this technology. I know you and your colleagues have looked at this in certain scenarios as well.

Manish Shah, MD: You described it very well. So, it's very exciting technology. It's a blood-based test to sort of track the disease. But here, it may be so sensitive and specific that we think that we might be able to make treatment decisions based on the presence or absence of this circulating tumor DNA. So, this is also an evolving field. The technology is great and now the applications are being studied. And there are clinical trials underway, some of which we're developing to try to better understand that. So, I think this will be a recurring topic over the next few years.

John P. Leonard, MD: Well, let's pivot a little bit here for our last few minutes, and I just want to recognize how podcasting and podcasts have changed. I think when I first got involved in this podcast, I, like many of you, was relatively unfamiliar, was just learning about what a podcast was, let alone how it could be interesting to me as a podcast consumer and also the potential as a podcast developer. I'm not going to use the term influencer by any stretch, but it's amazing to me over this time, how social media has changed and evolved. And I think we would all say in some ways for the better, some ways perhaps not as well as, or as good as we'd like. But clearly, podcasting and podcasts have become more and more a part of our society as a way to reach broad audiences of people who might find the content of interest. And also, ways that have become more and more simple. We've used a studio to help us put this together and hopefully make this enjoyable and entertaining and easy to use and access. But I think this field has really changed. And now, pretty much every day when I exercise or when I commute, I'm listening to one podcast or another. And the number of podcasts that are out there, the number of people and organizations and groups podcasting, has been exponential.

So, Dr. Shah, I'm so happy that you were taking over this particular podcast. Maybe, I know I and a few others on our team twisted your arm a little bit perhaps, but what is your kind of excitement around this and maybe a little bit about your vision of taking this forward?

Manish Shah, MD: No, nobody twisted my arm. I'm actually truly honored to even be considered for this. And I'm excited. I'm really quite excited. I think just as we talked about, and the time really has flown by on today's podcast. We've just touched on a few topics that have transformed cancer care. I feel like the pace of discovery, the pace of developing new technology is so fast that this is really a very nice forum for someone to talk about it with an expert like yourself or others to try to bring this new information to people who need it.

And it's a complex topic. This is not a topic that could be easily synthesized in a 30-second video on TikTok. I think this is something that we need to talk about and think about. So, I'm really quite excited to bring new topics to the Cornell community and beyond. There is going to be even more of an explosion in new technology and therapies as we talked about. Some of the things that I've mentioned along the way, but other things like artificial intelligence and how will that change cancer care, that's going to be an important topic we will kind of come in to. There are new technologies on how we can treat tumors. We've all heard about radiation and there's advances in radiation. But over the last eight months or so, the new technology is called histotripsy, where they use high energy sound waves to ablate tumors. And so, we could talk about things like that as well.

So, I'm really quite excited to bring this knowledge and excitement to everyone else. But also, as you said, as an opportunity to learn about new areas, as it may apply to the patients that I treat as well. So, I thank you very much and I'm really honored to take on this role. I expect that you will be coming back more than once, as you mentioned initially. Because I think it'll be exciting to continue this endeavor.

John P. Leonard, MD: Well, thanks very much, Manish, really for taking it on and for continuing and adding your own special insights and flavor for what's important out there, what's exciting out there, what people need to know about. I want to also thank our team for really putting this together. And over seven years, it's been a team of a number of different people and thank them for their commitment.

I also want to thank Weill Cornell Medicine and leadership and others who have supported this program. And finally, I just want to highlight the fact that I'll continue to listen and learn from Manish and all of the guests and the team here. And I think it's really important that patients and families and those working in the field have reliable sources of information. There's a lot of information out there. It's hard to get accurate information. Different people who are providing information might have different agendas, whether it's just trying to get people to click on a topic or listen to a topic or promote what they're trying to advance for their own reasons.

And I'm very proud and grateful to Weill Cornell Medicine, and all of those who have participated in this podcast for their efforts and commitment to making sure that this is a source of reliable, important, impactful information that patients, that the community, that the public can rely on, as they seek information about these important topics.

So again, thank you to our listeners for participating in this program because we know that there are a lot of people out there who have benefited and enjoyed this information. And hopefully, it's made an impact for your own individual circumstances, interests, and priorities.

I want to invite you to download, subscribe, rate, and review CancerCast on Apple Podcasts, Spotify, or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to see covered in more depth in the future.

That's it for CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. John Leonard. Thanks for tuning in.

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