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Dr. Manish Shah (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. Manish Shah. And today, we'll be talking about a new, specialized form of cellular immunotherapy called tumor-infiltrating lymphocyte, or TIL, therapy.

Our guest today is Dr. Barbara Ma. Dr. Ma is a medical oncologist at Weill Cornell Medicine caring for patients with skin cancers, including melanoma. Her research focuses on optimizing immunotherapy treatments for solid tumor patients, and she heads the Phase I Clinical Trial Unit here. Dr. Ma also leads cellular therapy for solid tumors at Weill Cornell, which makes her the perfect guest to speak about today's topic. Barbara, welcome.

Dr. Barbara Ma: Thanks so much for the warm welcome, Dr. Shah. It's a pleasure to speak with you and everyone today.

Dr. Manish Shah: We're really excited about this topic. It's a brand-new therapy, and I was very excited to hear that Cornell was one of the first institutions to implement it. So, we'll start with a little bit of background about yourself. How did you get into the field of oncology and what piqued your interest into research in immunotherapy for solid tumors?

Dr. Barbara Ma: So, it actually started off with family experience with cancer. My grandfather was diagnosed with lung cancer. And around that same time, my cousin was diagnosed with an ovarian teratoma. So seeing them go through their treatments of chemotherapy and surgery, I thought to myself, there really should be something treatment-wise that could harness the power of the immune system so that there's less toxicities with just as efficacious of a response. And that was when I got involved in my first research project, which I was lucky to have a mentor at Mount Sinai, who was doing research on oncolytic viruses -- or viruses that naturally target tumor cells -- and modifying it to enhance response. And that first foray into research really sparked a decades-long research career in immunotherapies or new ways to help enhance our own immune system to fight cancer.

Dr. Manish Shah: Well, that's wonderful. And if I remember correctly, you did your undergrad at Johns Hopkins. Is that right?

Dr. Barbara Ma: Yeah. So, you and I both share the same alma mater. So, I did biomedical engineering at Johns Hopkins. And then, I did my medical school at New York Medical College, did my residency at Georgetown, where I was lucky enough to learn from Dr. Michael Atkins, who's one of the leaders in immunotherapy in melanoma and renal cell carcinoma.

And then, I did my Cornell fellowship here, and I learned a lot under the tutelage of Dr. Anna Pavlick, who's also another melanoma giant. And then, more recently, I have been learning more from Dr. Jedd Wolchok and Dr. Paul Chapman when they joined us. So, we have a great melanoma team here.

Dr. Manish Shah: So, we used to treat melanoma with cytokines. For a long time, we knew that melanoma was somehow responsive to the immune system and the feeling was that if we could stimulate the immune system with some cytokines, you would have some regressions. And I remember, when we were on the wards giving this very, very toxic therapy to try to stimulate the immune system in melanoma.

In some patients with melanoma, you saw sometimes spontaneous regressions of the tumor. And the only way that could happen is by an activation of the immune system. And I guess that's a very basic primer of why we think that immunotherapy might be more effective in melanoma, but maybe you could talk a little bit about immunotherapy and then also cellular immunotherapy and broadly what those big topics are.

Dr. Barbara Ma: You bring up a very early start where they used to use something called high-dose IL-2. And that actually does lay some of the groundwork for the new TIL therapy that we're going to talk about. But I did want to set the landscape for how we treat melanoma. So, decades ago, all we had was chemotherapy. And really, it didn't work that well for melanoma. Response rates tend to be more in the order of like 5-10%, maybe a little bit higher if you do it in combination but didn't work very well and not long lasting. And it really wasn't until the advent of immunotherapy, with the first one being ipilimumab, an immune checkpoint inhibitor targeting CTLA-4 that was approved in 2011, that really transformed how we treat melanoma and subsequently other solid tumors.

So, immunotherapy, or more specifically immune checkpoint inhibitors, the analogy I like to make usually is if you think of your thermostat, there's always a mechanism. For example, if the temperature gets too hot, then your air conditioning kicks in to bring it down to a more regular temperature. Similarly, your immune system has this mechanism that whenever it sees a threat, a bacteria, a virus, or a cancer cell, it will rev up to activate and the immune system will rev up to fight off the threat. The immune checkpoints are the mechanisms that actually allow you to go from an activated immune system back to its regular state or what we call homeostasis. And the immune checkpoints serve as those breaks. So when we talk about immune checkpoint inhibitors, it's releasing the break to keep the immune system activated, and skin cancers do respond pretty well.

So, melanomas, about 60% of patients will respond well to immunotherapy and have a durable, long-lasting response. And so, that really did transform how we treat melanoma, other skin cancers and other solid tumors. And you do see immune checkpoint inhibitors used regularly in the treatment of stage IV solid tumor cancers.

So, that sets up the stage for how does TIL come in. So, there's still a significant portion of patients who would not respond to immunotherapies or need other options.

Now, there will be a subset of melanoma patients that have something called a BRAF mutation. And if they have a BRAF mutation, they are candidates for something called targeted therapy. So like, an oral pill that targets the BRAF mutation in combination with something called a MEK inhibitor. And now, while those response rates are higher, ultimately at some point, those patients develop resistance.

So, that's where TIL plays in, filling in this gap where we need another treatment option for patients who have progressed on prior immunotherapy and/or targeted therapy.

Dr. Manish Shah: So, you explained very nicely how immunotherapy works. The way that I think of it is that the immune system is revved up and ready to go to attack the cancer, but the cancer expresses proteins that kind of shields it from the immune system. And these proteins are called PD-L1 or PD-L2, or the ligand for CTLA-4. And then, the immunotherapies are antibodies that block that interaction from the cancer cell and the surrounding environment with the immune cells.

So, by blocking that interaction, you allow for the immune cells to activate, and then attack the cancer. So, I guess the first step is there's some cancers for which the immune system isn't revved up. And so, even if you block this interaction, sometimes the immunotherapy doesn't really activate the immune system enough to fight the cancer. That's why you have some cancers like melanoma that are very responsive to immunotherapy and other cancers like, some types of colon cancer, for example, are maybe less responsive to immunotherapy. I think that's very helpful. But then, what is cellular therapy?

Dr. Barbara Ma: So for the excellent explanation that you gave, you're talking about the immunotherapies, these are drugs. For cell therapy, it's more that the cells are drugs and actually more specifically using the patient's own cells. So, cell therapy is a new category. And some of the things that we may have heard of is CAR T or chimeric antigen receptor T-cell therapy.

The other one that I am going to talk about later is TIL, tumor-infiltrating lymphocytes. So, the difference is that both of these do use the patient's own cells.

For CAR T, it's actually isolating out the T cells from the patient's own blood and then modifying it to target a specific receptor, depending on whatever the tumor type is. For CAR T, the current approved indications are mainly in lymphoma, myeloma, so more the hematologic malignancies. There is not an FDA-approved CAR T for solid tumor as of yet. It hasn't translated as well.

That's where TIL plays a pretty exciting role because it is the first cell therapy approved for any solid tumor. And how TIL differs from CAR T is that TIL is taking a chunk of the patient's own tumor, isolating out tumor-infiltrating lymphocytes from there. And it's not modified in that you give it to the company, it takes about three to five weeks for turnaround. And then, they send it back to us to infuse back into the patient, but it's unmodified, whereas CAR T is modified.

Dr. Manish Shah: The way that I understand immunotherapy, we're basically blocking an interaction between the tumor and the microenvironment and the immune cell and allowing the immune cell to activate against the cancer. So for immune cell to activate against the cancer, it has to recognize the cancer and it has to be revved up to attack the cancer to kill it.

For CAR T therapy, the idea is that the immune cell can be modified in a way – that’s the chimeric receptor that’s created -- to recognize the cancer. So, that's one part of it. So, you take a patient's blood, you isolate the T cells and modify them by adding this receptor that now recognizes the patient's cancer. And then, you activate those cells and you give it back to the patient. So, that's what I think you're talking about with regard to modification.

What I was thinking about as you're explaining it is are you able to identify an antigen that is present on all the cancer cells that you can then give to the T cells and the T cells can recognize all the cancers? And so, for lymphoma, most of the CAR Ts recognize a common antigen, and that's why it works. But for solid tumors, there's no single antigen that's on all, let's say, melanomas that would work very well.

But the advantage for TILs is that you're taking the immune cells already present in a patient's tumor. And since they've already honed in on the tumor, they already recognize the tumor. So, you bypass that step and you only need to activate them. Is that a fair description of that difference?

Dr. Barbara Ma: Yes. For TILs, they already have those T-cell clones that exist that are personalized against your tumor, but there's usually something immunosuppressive in the tumor microenvironment that's preventing it from working. So, your CAR explanation is excellent. The TIL one's also great, but I'm going to refine it just a little bit. In that, when we're taking a chunk of the tumor, it almost seems like it's going in a black box and out pops some cells. But really, what they do in the company that makes this product, there's always a medical name and a brand name. The medical name is Lifileucel, the brand name is Amtagvi. The company that makes it is Iovance. So when the tumor gets sent to Iovance, they do isolate out these TILs. And then, they do give some inflammatory signals in the lab to help them expand and grow in number. When we're infusing it back in the patient, we actually do something called lymphodepleting chemotherapy, which are two drugs, fludarabine and cyclophosphamide, that we give to essentially make it easier for the cells to work. And part of it is they do remove some of those immunosuppressive factors.

When we talk about what's exactly in the TIL bag, it's actually a repertoire of many different T cells. We do think that CD8 T cells primarily drive a lot of the responses, but there is also CD4. And that is an active area of research about how can we make the TIL more efficacious. Are there certain T-cell populations that are responsible for it? And that's actually an active area of research that we're also doing here through our TIL Biobank that we've set up with Dr. Taha Merghoub and Dr. Jedd Wolchok's lab.

Dr. Manish Shah: Oh, that's terrific. So, practically, a piece of tumor tissue-- in this case, a melanoma-- is excised by a surgeon and it's taken and sent to the company. Now, the company will kind of digest that tissue and extract the immune cells that are in that tissue. And, for our audience, immune cells are white cells. That's what we think of. But the white cells are a whole host of different types of cells. And the way that we designate them is by the proteins that they carry.

So, there are a type of white cells that are called CD8 positive. So, these are proteins that are on these cells and they express this protein called CD8. And CD8-positive T cells, are the ones that are active in cell-killing against cancers.

There are other cells that might express CD4. And these are helper cells, and these cells help the immune response. And there are other cells that are B cells and those cells make antibodies. So, each type of cell is different. And somehow when you extract the immune cells, this whole panoply of cells, and you expand them, what you get back is a bag of cells that are infused into the patient. Some of these cells are really active against the cancer. And the research is to try to identify which cells are those, because then we could be a little bit more refined and maybe isolate just those cells and that would be even better. Is that correct?

Dr. Barbara Ma: Yeah, that's a great understanding of it. So, we're pretty excited about this therapy. And I think another point to also make is that the FDA approval, the indication, is for stage IV or unresectable melanoma patients who progressed on prior immunotherapy and targeted therapy if they have a BRAF mutation. And usually, the other treatment options, the response rates are low and/or not durable. But with this Lifileucel TIL, they did present the five-year follow-up data at ASCO and the response rate of 31.4% did play out into a durable response at the five-year mark of 19.7%. So, what that means is that 20% of patients still alive and well after getting this one-time treatment of TIL, like five years ago. And what's even more impressive is that even more than a year out after getting their TIL infusion, some of these patients had a deepening response, meaning that their tumor still continued to shrink even after getting that infusion more than a year ago. So, that is a very impressive signal and impressive response, and that actually makes us very excited about this new therapy.

Dr. Manish Shah: So back to the nuts and bolts, you take out the tumor, you send it to the company. The company extracts these immune cells, and we're not sure which ones of the many immune cells that are there are the ones that are active, but the beauty is that it doesn't much matter. You extract them all. So, the company gives these immune cells some activating drugs.

Dr. Barbara Ma: So then, we will give patients lymphodepleting chemo with the fludarabine and cyclophosphamide. And then, we do give the TIL infusion itself. And we do this in the hospital, because after the TIL infusion, this is where we give IL-2.

So, you had mentioned before that back in the old days, they did give a lot of high dose IL-2, which is an inflammatory cytokine. So now, we are still giving this high dose IL-2. And because of the toxicities, we do have to monitor these patients in the hospital. So, IL-2 is an inflammatory signal. We give the patients up to six doses every eight to 12 hours. And the main toxicities that we see are fevers, rigors, which is more like shaking because your temperature is high. We can also see low blood pressure and also nausea. But really, essentially, it's because of the toxicities from the IL-2 that these have to be managed by a team that's well experienced in giving IL-2 and managing toxicities for it.

Dr. Manish Shah: You get the infusion back from the company. And then, you prepare the patient with the chemotherapy to deplete the immune cells. And that allows for the TILs to be received better. And then, you give IL-2 to further stimulate these cells that are infused. That single treatment is all that's given. And then, you're saying that after that treatment, roughly 30% of patients have a response to that treatment-- a response, meaning a shrinkage in their tumor. And 20% of them, so two-thirds of them, have a durable response, meaning lasting even up to five years so far and ongoing. So, it could be that a significant proportion of people are even-- I mean, we don't like to use the word cured, but long-term durable response without recurrence of disease after a single treatment of TIL therapy. Is that right?

Dr. Barbara Ma: Yeah. So, it's very exciting. The chance that a durable response or a functional cure is a pretty exciting one. And this is why this was FDA approved February 16th, 2024, just for this indication of progression after prior immunotherapy and targeted therapy. It's meeting a huge unmet need.

Dr. Manish Shah: That's incredible. I know we've given it to patients here at Cornell. And thanks in large part to your efforts here, which is great. But why don't we take a minute and talk about where this field is going. What's the research that excites you about TIL therapy? I think you mentioned a little bit like maybe identifying the subset of immune cells that are actually the real actors here. But what else is there that's exciting?

Dr. Barbara Ma: When we think about how to make TIL better, one thing is also how to reduce the toxicity. So, whereas the other immune checkpoint inhibitors that we talk about, you can face some chronic toxicities that require steroids for weeks. Actually for TIL, most of the toxicities are surrounding the lymphodepleting chemo and the IL-2. And the difference is that these toxicities are short-lived, mainly resolved within two weeks. And that is one key point. But still, how do we make it more tolerable so that they don't face the toxicity from IL-2. So for next generation approaches, there are other groups that have been focusing on IL2-sparing approaches such as targeting a different receptor, for example, IL-15.

Dr. Manish Shah: Because you're giving back the patient's own immune cells that are activated, there are some toxicities to immunotherapy, like colitis or pneumonitis or thyroid or adrenal problems. Do you see that with TILs? I would expect not.

Dr. Barbara Ma: You do not, because it's a different mechanism. And actually, even this is different than the toxicity of CAR T. Whereas CAR T it's very common to see some inflammatory syndromes, such as cytokine release syndrome and something called ICANS, which is an immune effector cell-associated neurotoxicity syndrome. You don't actually see that with TIL. TIL, it's mostly low blood counts from the chemo that you give the week before. And then, fever, chills, the kidney function bumping up, those are the toxicities that we commonly see with IL-2.

Dr. Manish Shah: That's really amazing. I think it sounds like it's transformative advancement in terms of a new type of therapy that essentially uses the patient's immune cells, but isolated and activated.

Dr. Barbara Ma: One of the other things is that we're also trying to see this approach in other solid tumors. So, for example , one of the trials that we are getting set up here is also the Iovance Lung trial using the Lifileucel TIL in lung cancer patients. And they have tried this also in other solid tumors like endometrial, as well.

So, I think, where the field is heading towards is trying to actually herald a new era, how melanoma was the initial poster child with immunotherapy. I do think that melanoma is leading the way also for cell therapy as a treatment option for other solid tumors.

Dr. Manish Shah: Well, that's terrific. And, I think, from the origins of how you thought about activating the immune system when you were younger, and you're seeing your relatives go through this, I think it's very rare in a single lifetime or career, you see such a transformative application. I'm really quite impressed.

Dr. Barbara Ma: I did not imagine how far we could progress in terms of cancer treatments, you know, just within this lifetime. But I also think that the melanoma field, as a whole has also been very excited about a more powerful way to harness a patient's own cells to fight cancer.

Dr. Manish Shah: That's wonderful. Well, Dr. Ma, thank you so much for your time today. I think this was quite informative. And thank you for all that you do. And thanks to research that's funded to support the development of this kind of work. I know that this was largely done by a guy at the NIH called Steve Rosenberg, who was doing this 25 years ago. And it took that long to develop this into such an incredible new treatment.

Dr. Barbara Ma: Definitely. It's really a multidisciplinary effort. It does require coordination with our excellent BMT group here as well as our TIL surgeons and the melanoma group and the coordinators, as well as Dr. Merghoub and Dr. Wolchok’s lab and the exciting research behind this as well. So really, a multidisciplinary effort that we're really happy to partake in. So, thanks so much for this invitation to talk here and share about this.

Dr. Manish Shah: Wonderful. So, with that. We'll end. You can download, subscribe, rate, and review CancerCast on Apple Podcasts, Spotify, YouTube, 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 hear us cover in the future. That's it for CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. Manish Shah. Thanks for listening.

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