John Leonard, MD (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. John Leonard. And today on the podcast, we will be talking about a type of cancer treatment that has become very important in the field, and that is called immunotherapy.

It's really a great pleasure for me to have with us today as our guest, Dr. Jedd Wolchok. Dr. Wolchok is the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian Hospital. He is a medical oncologist who specializes in the treatment of melanoma. His work has really helped to establish immunotherapy as a standard treatment for cancer. And Dr. Wolchok was instrumental in the clinical development and many of the laboratory developments leading to the approvals of the immunotherapy, particularly ipilimumab, as well as the combination of nivolumab and ipilimumab for advanced melanoma.

Dr. Wolchok is highly involved in cancer research. He manages a lab which investigates new immunotherapies and their role for the treatment of cancer. He sees patients with melanoma and other malignancies and also, very importantly, is the director of the cancer efforts here at Weill Cornell in collaboration with NewYork-Presbyterian Hospital. Dr. Wolchok's role here at our institution is very important and broad. But today, we're going to focus primarily on the area of immunotherapy and its impact for patients. So, Jedd, thanks so much for joining us today. It's really great to have you here.

Jedd Wolchok, MD: It's a privilege, John. Thanks for having me.

John Leonard, MD: To start off, you have over your career focused on cancer, melanoma and immunotherapy, kind of in different levels and different ways and impacted those fields tremendously. What led you to focus in these areas in particular? What really led you in these directions?

Jedd Wolchok, MD: Yes. Like many people, John, it was really the death of some family members from cancer at formative points in my own career development that were the inspiration for me to think about a career in cancer care and cancer research.

I actually at the end of high school, beginning of college, was a summer student in a laboratory here at Weill Cornell studying immunology. And that was a very important part of my career development. And then shortly thereafter, I was involved in a laboratory at Memorial Sloan Kettering looking at immunotherapy for melanoma, treating melanoma with an antibody. And I hadn't really known very much about melanoma. I didn't really know very much about immunotherapy, but it was really the idea that we could approach a difficult disease with a new kind of therapeutic option, and that laboratory research was relevant in bringing that new therapeutic option to patients that really got me hooked on the field.

John Leonard, MD: Let's start at the beginning or with some of the basics and then kind of move forward from the standpoint of the different subtypes of immunotherapies. So, people are used to radiation therapy. They're used to surgery. They're used to chemotherapy. All of those have good and bad things about them depending on the context. How would you describe immunotherapy broadly, and then maybe you could focus a little bit on the concept of why this makes sense to approach, at least in certain cancers?

Jedd Wolchok, MD: Immunotherapy has become a pretty broad topic. And actually, the best way to think about it is that it is a somewhat indirect way of treating cancer. We're used to treatments that focus on the cancer cell itself as the target, such as chemotherapy or radiation, where the goal of that therapy is to simply stop the cancer cell from dividing. Immunotherapy seeks to use the power of the body's immune cells, whether they be T lymphocytes, B lymphocytes or what are termed the innate immune cells, things like macrophages or NK cells, as really the therapeutic modality to try to kill the cancer cells. So, the idea of immunotherapy is to, at some level, use the body's own immune cells as the weapon against the cancer.

And, really, I would say one of the first successful immunotherapies in the field that you are a luminary in, in the treatment of B cell lymphomas, where the use of antibody therapy, specifically antibodies that target the CD20 molecule, really were the first example of immune-based treatments causing meaningful regressions and disease control in cancer.

Antibody therapies -- meaning antibodies are proteins that the immune system produces that latch on to targets on the cancer cell in this case, and then enable recognition like little flags on the surface of the cancer cell for other immune cells to come along and to essentially kill the cancer cell. Certainly, B cell lymphomas, breast cancer with medicines that flag the HER2 molecule on the surface, as well as other targets on other cancers have made antibody-based treatments a very commonly used cancer therapy.

The area of immunotherapy that I have spent the largest proportion of my career studying is something called immune checkpoint blockade. And this is an area that took many decades of very careful basic science research to evolve. It really relied upon an understanding of what are the molecular switches that turn our immune system on and off. And, as it turns out, there are a whole series of these molecular switches, which we now call immune checkpoints, that keep the immune system from running out of control.

And you might say, "Well, why would that be necessary? Isn't the immune system only something good for our bodies?" And the answer is “no, that's really just part of the story”. The immune system certainly can potently protect us from pathogens and from cancer. But if the immune system is not regulated in an effective way, we can end up with damage to normal body parts, things like autoimmune diseases such as ulcerative colitis, multiple sclerosis, lupus, psoriasis. These are all examples of the immune system running a bit out of control and causing damage to normal body parts. So, the immune checkpoints are a series of pathways that tamp down the immune system after it's been activated.

And I had the great privilege about 25 years ago to interact with one of the real prime movers in the field of immune checkpoints, a scientist by the name of Jim Allison who discovered one of the first immune checkpoints called CTLA-4. And Jim really thought that if you could block this immune checkpoint, allow the immune system to operate at a higher level than these checkpoints would allow, you could overcome any immune-suppressive influence that the cancer was using to hide from the immune response. And that was really the basis for the drug with this almost unpronounceable name, ipilimumab. I have to admit that I had to stand in front of the mirror and pronounce it syllable by syllable each time.

Jim always made the joke that since the foundational work for the development of ipilimumab was done at University of California, Berkeley that it would have been right and proper for the FDA not to call the drug ipilimumab, but rather hippy-limumab. Sadly, there was no such nod to the lineage of the discovery. But there are now many immune checkpoint blocking drugs for the CTLA-4 pathway and for another pathway called the PD1 pathway. And these PD1-blocking drugs have really become incorporated into the treatment programs for a variety of different cancers.

A new area of immunotherapy really holds a lot of promise and is at the relative beginning of its development is cell therapy. And this is a kind of treatment where instead of giving an IV with a protein like an antibody in it that blocks the immune checkpoint, we're actually giving the patient essentially a transfusion of cells. And those cells recognize a target on the cancer, and they respond to that cancer cell and kill it. This is actually the basis for allogeneic bone marrow transplantation, which has been used for many decades to treat leukemias and lymphomas.

And more recently, there have been approvals of what are called CAR T-cells, which are engineered immune cells that have been essentially genetically programmed to recognize specific targets on the cancer cells, as well as just a few months ago, a kind of therapy called tumor-infiltrating lymphocyte therapy, which is a kind of complex treatment plan where a patient undergoes a surgery to remove a tumor. The tumor cells are separated from the immune cells that were present in in the tumor. Those immune cells are sent to a laboratory where they are expanded over a few weeks and then given back to the patient as essentially a transfusion. The patient also receives chemotherapy to try to make space in the immune repertoire for this transfusion of their own immune cells. And in some people, say, with diseases like melanoma that don't respond to the checkpoint-blocking therapy, this type of treatment has caused meaningful regressions. And I'm very happy to report that here at Weill Cornell and at NewYork-Presbyterian Hospital, we are among the first places to offer this kind of treatment to our patients now that it's been commercially approved. And we have actually treated the first two or three patients already in just the first few months after the FDA approved the treatment.

John Leonard, MD: That's a great summary and very, very helpful, I know, for the audience just to kind of get a sense of how the field is evolving and the rationale for it. Maybe you could comment on the key tumor types at a high level where at least the checkpoint inhibitors have had the greatest impact so far. And then, maybe, I know a lot of your work is trying to improve and understand how these approaches work. What do we know about it? And I know this is an age-old question in cancer, why does a treatment work in one cancer and not another, or one patient and not another with the same diagnosis? What are some of the factors that figure into that, at least as we know them now?

Jedd Wolchok, MD: It's a critically important question, John. And so, the diseases where immune checkpoint inhibitors are commonly used include metastatic melanoma, which is the disease that I treat most often; kidney cancer, bladder cancer, lung cancer; some kinds of lymphoma, Hodgkin lymphoma, to be specific; some kinds of breast cancer, a subtype called triple-negative breast cancer. Some of the upper gastrointestinal cancers like stomach and esophagus cancer, as well as cancers of the head and neck area. Some advanced squamous cell skin cancers when they can't be controlled with surgery alone. And some other rarer cancers such as a rare skin cancer called Merkel cell carcinoma is another cancer that is treated with immune checkpoint blockade.

Well, what do many of these diseases have in common that allows us to understand why this treatment works in these diseases and not in others? If we think about some of the more common cancers on that list that I just gave of melanoma, lung cancer, and bladder cancer, one feature that these cancers share is that they are among the most heavily mutated cancers.

So now, as many people know, it's quite common for people's tumors to undergo genetic sequencing to determine what therapies may be available to them based upon precision medicine approaches. And one of the things that we've learned is that melanoma, lung cancer, bladder cancer, have very high mutation burdens, so they have many more genetic errors than other kinds of cancer. And we believe that that is the case because these diseases result from chronic exposure to specific carcinogens. In the case of melanoma and other skin cancers, the carcinogen is solar ultraviolet light, so sun exposure. And in the case of bladder and lung cancer and head and neck cancer, many of these cases, but not all, are related to the carcinogens that are found in tobacco smoke. And so, the chronic exposure to these carcinogens causes a very heavily mutated genome in the cancer cells.

Now, why is that important? Well, that's important because our immune systems are programmed to tell the difference between self and not-self. And that is really the basis for their ability to recognize bacteria and viruses and to not attack normal tissue. And so, cancer really sits somewhere in between self and non-self. One of my mentors, Dr. Alan Houghton best described cancer as altered self. And the degree to which it's altered really seems to convey an influence on how likely it is that immunotherapy will work. So, the less a cancer resembles the normal cell that it came from, the more likely it is that immunotherapy will have an impact. And so, since all of these genetic mutations give rise to abnormal or non-self-appearing proteins, the immune system may think that a given cancer with a very heavily mutated genome looks less like the normal skin cell that it came from in the case of melanoma, and more like a bacteria or a virus. And therefore, it is more likely to form a reaction against it.

John Leonard, MD: Thank you. And that makes a lot of sense from the standpoint of self-recognition and being able to turn on the immune system. The next step in immunotherapy seems to be in many situations, combinations, and it makes sense that there are combinations of immunotherapy drugs that will turn on different arms or different aspects of the immune system to make them work better. My first question around this topic relates to, do we see a lot more toxicity and side effects with those combinations? It would seem likely that when you give two drugs, it tends to be more toxic than one in almost every situation.

And then, the other kind of follow-up question would be, we often combine with chemotherapy, and as many people know, chemotherapy suppresses the immune system in some ways, sometimes. That would seem to be kind of counterproductive. On the other hand, if chemotherapy kills tumor cells, that might help the immune system along in one way or another. How do you think about those areas and combinations? Because it seems like very few times now are we using just one drug. I'm sure your laboratory work in some cases informs those directions, as well.

Jedd Wolchok, MD: Yes, that's exactly right. So, in terms of the simplest combination, which would be one immunotherapy with another immunotherapy, such as some of the treatments that we use for melanoma, for example, the combination of ipilimumab with nivolumab, both of those agents will converge on the T cell as really the ultimate therapeutic modality that kills cancer cells. However, the way that they get there is by different pathways, and so there's value in combining them. When we give, say, ipilimumab by itself, it may help, like, 10% of people with melanoma. If we give nivolumab by itself, it may help, like, 40% of people with melanoma. But when we give them together, not surprisingly, we get between 50% and 60% of people showing responses to that combination. We also get much more toxicity when we give both of them together. We see much more frequent appearance of immune-related side effects when we give two medicines together versus one.

And I should mention that the side effects that we see with immunotherapy are very different than what we see with chemotherapy. We don't see the nausea, vomiting, hair loss, blood count suppression that are so common with chemotherapy. But we do see inflammation in the skin, in the colon, in the liver and some of the endocrine glands in the body that really remind us actually of autoimmune disease rather than the classical chemotherapy toxicities.

And over time, we've become more adept at managing these side effects, and we actually rely upon input from other medical subspecialists for optimal management of these toxicities. So, we collaborate with gastroenterologists and with endocrinologists and pulmonologists. And actually, that is really one of the real perks of working in such a robust academic medical center like Weill Cornell/NewYork-Presbyterian where we have such a deep bench in many different areas of medicine that allow us to collaborate so effectively.

Now, your question about chemotherapy-based combinations, which are quite common in diseases like lung cancer, it's a very frequent use of chemotherapy plus PD1 blockade immunotherapy in lung cancer as a first-line treatment. You're correct that at first blush, it would seem to be counterproductive to make these combinations. But the immune suppression that we see with chemotherapy is actually quite short-lived. It lasts a week or two. And then, there's actually a period of time when the immune system is recovering from that insult of the chemotherapy where the immune cells are actually dividing really quickly and reconstituting the immune compartments, and that's a very favorable time for immune modulation with, say, checkpoint blocking antibodies. So, those combinations actually have, thankfully, been additive and not in any way an impediment.

John Leonard, MD: So, you are at the cutting edge of this field. And clearly, this is a big strength of the programs at Weill Cornell and NewYork-Presbyterian as well. What does the future hold? Are we going to see immunotherapies in more tumors? Are we going to see them work better? Are we going to see more combinations? You've alluded to the key areas, but what will it look like in five years, say, as far as where things are going?

Jedd Wolchok, MD: I do wish I had a crystal ball, to be honest with you. But I think that what we hope to see is the development of cell therapies for some of the more common solid tumor cancers. You know, the success of cell therapies have really been in the hematologic cancers that are your expertise. And what we're hoping is that we can make some inroads into identifying targets in some of the common solid tumors for cell therapy. What we'd also like to see is another generation of immune modulators that rather than cutting off the brakes, such as the checkpoint blocking antibodies, stepping on the gas. So, the agonist agents, which have not been very easy to develop because they actually have to be in some cases administered into the tumor, rather than intravenously, to be given safely.

The other area that's of great interest to many people here at Weill Cornell actually is an area called immunometabolism and this builds upon some strengths that the institution has, understanding the importance of our body's metabolism and the tumor cells' metabolism to develop new therapeutic avenues. For example, there has been a lot of work done to try to understand what the role of sugar use is in controlling cancer growth. And certainly, many people are aware that PET scans are based upon a metabolic phenomenon called the Warburg effect, which basically shows that cancer cells use a lot more sugar than normal cells. And that has actually led to some proposed dietary interventions where people limit their sugar intake as a way to try to control cancer. And while that's a very logical step to take, we also need to remember that our immune cells, normal cells, need sugar to do their job well.

And actually, one of the faculty members here at Weill Cornell, Dr. Roberta Zappasodi, has done some really elegant work in variety of different cancers to show that the availability of sugar inside tumors is critically important for immune recognition, that if there's inadequate sugar inside a tumor, immune cells can't work well. And actually, by making more sugar available to the immune cells, we may actually help blunt the influence from some unhelpful immune cells called regulatory T cells. So, this turns out to be a very complicated balance between sugar uptake by the cancer cell to drive its thirst to divide and the need of normal cells like immune cells to keep their metabolism moving with sugar utilization. So, I think that what we're going to see is a refinement of current combination strategies that take advantage of things like diet and metabolism to optimize currently available and future immunotherapies.

John Leonard, MD: I think hearing you tell that story, whoever came up with the Goldilocks story, I think, really nailed it from the standpoint of not too much, but not too little.

So, before we wrap up, any other areas that you want to just mention that people should keep an eye out for here at Weill Cornell and NewYork-Presbyterian about programs, projects, research, or novel approaches relating to immunotherapy that are either in the clinic that we haven't touched on or on the horizon soon, including clinical trials perhaps?

Jedd Wolchok, MD: We're always eager to develop new clinical trials because we are interested in science for science's sake, but we're also, of course, most committed to pursuing science that leads us in new therapeutic directions. And so, one area that I think brings together many of the best features of Weill Cornell and NewYork-Presbyterian is precision medicine.

We've learned that precision medicine, really based upon gene sequencing, has led us to a panel of new targeted therapies that specifically block pathways that drive abnormal signaling inside cancer cells that lead to their division. What we're hoping now is that we can use the same kind of platforms to understand not just how the cancer cells are working in a given patient's biopsies or surgical specimens, but to understand what the immune landscape looks like so that we can not only predict what targeted inhibitors to use for a given patient, but to understand which immune levers need to be pulled, whether they are agonists or antagonists, whether we need to supplement the immune repertoire with modified T cells or expand tumor-infiltrating lymphocytes. What I hope is in the next five years, we'll be able to approach immunotherapy with a degree of personalization and precision medicine mindset that we have used for the targeted therapies.

John Leonard, MD: So, a takeaway for a patient who is dealing with cancer, what would you advise them, you know, ask their doctor about immunotherapy, look in clinical trials, what's the key take-home message from a patient's perspective?

Jedd Wolchok, MD: I think the first take-home is that immunotherapy has joined the list of standard foundational approaches to cancer treatment in the last 10 years, alongside chemotherapy, targeted therapy, radiation therapy, and surgery. And that's a milestone for the field that people should be aware of, that the treatment options are now expanded. And absolutely, patients and their family members should speak with their clinical teams about whether immunotherapy is a rational choice for them. And also, even if it's not an approved therapy, are there clinical trials that would be relevant to consider for the patient to pursue if standard approaches are not providing the optimal outcomes.

John Leonard, MD: Well, Jedd, thank you so much for joining us today. You're a great colleague here at Weill Cornell and NYP. It's great to hear you explain this field in such an accessible way for our audience. And thanks for all of your contributions. It's made a huge difference for patients.

Jedd Wolchok, MD: Thank you, John. And thank you for having me. I really appreciate it.

John Leonard, MD: I'd like to invite our audience 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 us cover more in 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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