Dr. Ma: [upbeat music] 25 years ago, metastatic melanoma really was a death sentence.
Erin Welsh: Dr. Barbara Ma is a medical oncologist specializing in the treatment of melanoma. She also leads cellular therapy for solid tumors at NewYork-Presbyterian and Weill Cornell Medicine. Because of the complex biology of melanoma, treatments like chemotherapy that work for other cancers aren't effective.
Dr. Ma: You really had no good treatment option. When the first immune checkpoint inhibitor was FDA approved, that was actually when you really saw change.
Erin Welsh: The introduction of immune therapies created a new pathway for patients with melanoma and other types of solid tumors to achieve a functional cure for a once-deadly disease, but there was a gap.
Dr. Ma: If you were not part of the 60% that had durable response to immunotherapy, you effectively lost a chance at a cure.
Erin Welsh: Even with immune therapy, the disease continued to progress in about 40% of patients.
Dr. Ma: We just have no more options for cure until lifileucel tumor-infiltrating lymphocyte therapy, which is the first cell therapy for any solid tumor. In February 2024, it was FDA approved for melanoma. It is a complex multi-step process that involves procurement, isolating the TIL cells from a chunk of tumor.
Erin Welsh: These powerful cells from the patient's own tumor are cultivated in large quantities in a lab, then infused back into the body. These reinforced cells can attack the patient's tumor directly in greater numbers.
Dr. Ma: There were patients years out, if they had stable disease, it could deepen to a partial response, or if they had a partial response, it could deepen to a complete response, and that is amazing.
Erin Welsh: Patients with metastatic melanoma whose cancer has continued to progress now have a renewed chance at a cure.
Dr. Ma: It can only be administered in certain specialized centers right now because of the complexity in the process to get it administered in a consistent way. A lot of science, you really move forward multidisciplinarily, especially since this is so multi-step, complex, and requires a lot of players. It really needs a collaborative system to make this consistently work, and I'm very lucky that Cornell has that environment for us to all effectively work together.
Erin Welsh: [upbeat music] I'm Erin Welsh, and this is Advances in Care.
Today, I speak with Dr. Barbara Ma about this incredible paradigm shift in treatment for metastatic melanoma and how her team is innovating cell therapy through clinical trials to push the field even further.
Erin Welsh: Dr. Ma, thank you for joining me today. It's great to have you here.
Dr. Ma: Thanks so much, Erin. I appreciate the invitation.
Erin Welsh: To start us off, I would love to hear more about your career journey. How did you find yourself first drawn to oncology and then more specifically to these types of therapies, these immune and cell therapies?
Dr. Ma: So that actually brings us back a couple of decades, and I swear I'm not that old. But, uh, [laughs] actually, when I was a high school student, I do remember reading that cover issue of Scientific American, where they actually first talked about the concept of oncolytic viruses. And I thought it was pretty neat because you think of viruses as nature's most effective assassins, and using it and harnessing that power against nature's greatest enemy, cancer, I thought that was a really neat idea. And so that's why I really, [laughs] really thought more about how interesting it was to try to think about immune-based therapies. Coming to fellowship at Cornell and staying on as attending, that's where I really started diving more into immune-based therapies. It really is about how can we use our own immune system to effectively kill cancer cells, and I kind of see cell therapy as actually the next wave of new class of therapies, um, that's really focused on how can we harness the power of our own immune system.
Erin Welsh: Definitely. And speaking of that, can you tell me about what some of the challenges have been with administering immunotherapy for melanoma and other types of solid tumors?
Dr. Ma: So, for immunotherapy, meaning the immune checkpoint inhibitors, toxicity is still an issue. There is a unique class of toxicities that we call immune-related adverse events, which are really more inflammatory or autoimmune-like in nature that requires management with steroids, which can limit the effectiveness of immunotherapy. For some of these immune toxicities, they can be chronic, uh, meaning they could get immunotherapy-related hypothyroidism or immunotherapy-related adrenal insufficiency, and some of these chronic toxicities can be quite troublesome for some patients. With cell therapy, with lifileucel TIL, we don't really see too much side effects from just the TIL infusion itself. There could be delayed toxicities seen, but not to the same degree or nature as we see for the immune-related adverse events in immune checkpoint inhibitors.
Erin Welsh: I mean, this, this approach seems pretty game-changing, particularly from a patient perspective. And so obviously, TIL therapy has garnered a lot of well-deserved attention lately, especially after becoming one of the first FDA-approved cell therapies for these notoriously hard to treat solid tumor cancers. Can you take me through the process of how TIL therapy is performed?
Dr. Ma: So, tumor-infiltrating lymphocyte, they are fighter cells that are very specific for your own tumor. They are tumor-reactive T cells, and it's a multi-step process that first starts with a tumor procurement, and that first step usually involves surgeon. After sending out that tumor sample to the cell therapy lab, who then isolate out those TIL cells to prepare as a cell therapy product to give back to the patient. When the cell product is ready, which takes about five weeks, then we administer lymphodepleting chemotherapy.
Erin Welsh: And so these lymphocytes already exist in, in your cell, and it's just sort of giving them a boost to help them work?
Dr. Ma: There's usually something immunosuppressive in the tumor microenvironment that's limiting them from working. So, when you give the patient the lymphodepleting chemo, it actually is facilitating this environment that allows the TIL to come in and, and work better. We give the TIL, and then we give something called IL-2.
Erin Welsh: And I understand that IL-2 really revs up the body's immune response, which helps those amplified TIL cells from the infusion to attack the patient's tumor effectively. But IL-2 can also make people very sick because of that immune revving response.
Dr. Ma: Yes, and think about it as, like, a inflammatory cytokine that really activates those cells, basically expands those TIL cells in vivo in the patient. It can also be quite toxic, so that's why we have to do that in the hospital setting. You do need an authorized treatment center to get comfortable with managing the tox, but also operations-wise, you need a consistent system.
Erin Welsh: And so the, the challenges with IL-2 is really trying to, like, strike this balance where you want to reduce the toxicity to increase tolerability, but not reduce the efficacy of IL-2. And so what have you learned so far about striking that balance?
Dr. Ma: So you do need some IL-2. The thought used to be that you gotta push all six doses to the point that, you know, they're super, super sick, you know, must be in ICU. But I, I think from the findings in our, uh, meta-analysis, that is not the case. I think it also just underscores that you dose the IL-2 to tolerance.
Erin Welsh: When someone undergoes TIL, from the patient perspective, they have the surgery to remove a bit of the tumor to then extract this, and then what's, what's the experience like after those five weeks have passed and the infusion is ready?
Dr. Ma: We try to do the procurement from, like, a easily accessible site, so it's, uh, usually, like, a short recovery. We do admit our patients starting from the lymphodepleting chemo. The TIL infusion itself, you may get, you know, some inflammation of some sort, but it's usually generally, uh, well-tolerated. It's more the IL-2 that is usually the most, like, active part of the admission. It's very common to have fevers, chills, rigors. So you do need an authorized treatment center to get comfortable with managing the tox. On average, for us, it's more like a two-week hospitalization, and then after discharge, I do see them weekly post-hospitalization until we get the first set of restaging scans at the six-week mark.
Erin Welsh: Gotcha. And so, you know, when it comes to success with TIL therapy, how is that measured? Like, what percentage of patients see a response in some way?
Dr. Ma: In the first real-world study that we were a part of, the response rate for that was 44%. And then we also have to keep in mind the landscape, 'cause remember, what were the options before lifileucel TIL? It was a trial or chemo. To put that in context, you have to know what are the response rates for that. So for second-line chemotherapy, it's usually still on the order of, like, teens, you know, for the percentage, if not single digit, and chemotherapy's not durable. So you're only buying, like, till the next scan, right? So that would be just, like, three months if, if even. We need there to be persistence. There, there needs to be the T-cell that is, like, long-lasting, right? There needs to be, like, a, a memory T-cell that's keeping the, the tumor at bay. But for the pivotal trial that got TIL-approved, response rate was 31.4%, but you were kind of fighting against, like, 11%, so or, like, 15%, so 31.4% is a, is a big deal.
Erin Welsh: A huge deal.
Dr. Ma: Especially if long-lasting.
Erin Welsh: Yeah.
Dr. Ma: For lifileucel TIL, when we see that, okay, we got this response rate, but also that it can last, that's actually what's exciting. This is the multi-step process, but why did it get FDA approved is that they were able to see durable responses, and actually, it represents another chance at a potential cure, especially in patients who've progressed after prior immunotherapy.
Erin Welsh: Yeah, that is, that is so encouraging. And you've mentioned a couple of patients. I was wondering if you could share more about a particular patient's journey that really impacted you in some way.
Dr. Ma: All of them are very special to me. It's always a privilege to be a part of their journey, and I, uh, don't take that trust lightly because it's a time where you're mentally struggling, and it's... The patient's not the only person involved in it. It's also their whole family. And the very first patient that we treated, it was fifth line for him. You're, like, usually not as optimistic because, uh, cancer's smart. But lifileucel TIL had just gotten approved. We were able to get him harvested pretty quickly. When he got through, you know, TIL and the doses of IL-2, he recovered really nicely. He's two years out, and actually, it's, um, still shrinking. But he always tells me that, you know, it's like another chance at life, and he's back to doing his hobbies.
Erin Welsh: Yeah, I mean, that is wonderful to witness in real time how this research integrates with patient care. So where do you see this therapy fitting in in terms of when it should be considered during the disease course?
Dr. Ma: I do think that earlier line tends to be better, so we were part of the first real-world study, and we showed that actually, uh, patients tend to do better if they were earlier line of treatment and lower disease burden. So it actually does underscore the importance of early referral and trying to get these patients earlier. So I would say to try to get these patients in the second line 'cause I think they'll, they tend to do better. The other thing is that even though this has been a monumental advance, I do think that education is quite important. We have to reinforce with people that this is an FDA-approved therapy, and currently, you know, we can just mainly access these in the specialized academic authorized treatment centers, but for the community, they do need to be aware about this and also about earlier referral.
Erin Welsh: Mm-hmm. Just to be able to expand it to more, more patients, and then we have more information, more opportunities to optimize and, and reform these, these therapies.
Dr. Ma: Yeah.
Erin Welsh: And I want to talk about where TIL therapy might go in the future. So there's, it's been ground truth. It's very promising. The next step is now improving and optimizing. What are some of the areas that you're doing work in in terms of how can we make TIL therapy better?
Dr. Ma: We do have some ongoing investigator-initiated concepts. For example, what is something that can shorten the manufacturing time? So that's actually one of the clinical projects that we're working on. And, uh, another aspect is IL-2 sparing. You know, TIL is a one-time multi-step process, but you do have to be fit enough to tolerate the lymphodepleting chemo and the IL-2. There is an IL-2 sparing next gen trial that is coming later this year, so we will be the flagship institution for that trial. It's more based on different cytokines, IL-12 and IL-15, but that's something that I think is exciting because I do think that we're gonna be looking at ways to, like, minimize the toxicity. So, that I think is something important because, you know, if we make it less toxic, less intensive, do something to make a better product, then we may be able to expand the cell therapy eligible population.
Erin Welsh: Yeah, I mean, that would be wonderful to be able to broaden access and have more patients able to get TIL. And so for immune therapies like this, you mentioned that there are certain types of solid tumor cancers that are more immune responsive. Are there other cancers where you feel like this could go next?
Dr. Ma: Lung cancer, that's one. Head and neck, cervical, endometrial, those are all being actively looked at. I, I think the other key is, like, what about the traditionally immunologically cold tumors? You know, can we make them more responsive to it? So I, I do think that some of the trials that are ongoing are actually trying to answer that, but I would tend to think that the more traditionally immune responsive ones are probably where we'll see the signal next.
Erin Welsh: Yeah, it is amazing to think about TIL being used to treat these other types of cancer. And as we've discussed, NewYork-Presbyterian is really on the cutting edge here, both in terms of administering TIL and pushing forward research for how to optimize it. How does the collaborative culture here make that possible?
Dr. Ma: To really consistently give this, you need a consistent process. You have to have streamlined workflow for referral, intake, workup, finance clearance, and I, I think this is one of the barriers operationally and logistically for some of the centers. You need a lot of buy-in from many different players, and, uh, I think the key point is actually communication. NYP gathered a number of key players that work well together and communicate effectively, and we have buy-in not just from each of the disease teams, but also from our institution. And to have us be able to consistently deliver the system is actually what allows for success. One of the joys in, in working at Cornell is actually really, like, what a great team we have, you know, from the surgeon to the cell therapy to not just the attendings, but also the, the nursing, the pharmacists. This really is multidisciplinary, and it really takes a village, and I, I think we have a really special group here, so I'm very privileged to be a part of it.
Erin Welsh: You know, as someone who's involved heavily in, in clinical trials of cell therapies, of, um, immunotherapies, what do you see as the most exciting developments on the horizon, maybe in the next five to 10 years?
Dr. Ma: I really think that cell therapy is the next frontier. So ways to make cell therapy more accessible to the bigger population, whether that be outpatient lymphodepletion, faster manufacturing time, less of an intense, you know, or maybe no IL-2. I actually do think that that's the, the future. And when we think about cure, right, we start thinking about how can we get away with less, meaning what can we do with, like, less toxicity? And I actually think that that's an exciting place to be. And the fact that cell therapy gives another shot at cure and, you know, it also allows us to think about, okay, as we start seeing more of these, you know, durable responses, what are ways that we can really mitigate the toxicity and get by with things that are actually better for quality of life? So I think that is probably where we're gonna be heading next as we start seeing more advancements for this next frontier.
Erin Welsh: I mean, it seems like such an exciting field to be in and to, to see all of these changes happening so quickly. And Dr. Ma, I just want to thank you for such a hopeful and fascinating conversation. I'm, I'm thrilled to see where this new therapy goes.
Dr. Ma: Yeah. Thanks so much for the invitation, Erin. I really appreciate sharing about this, my favorite topic [laughs]. [outro music]
Erin Welsh: Thanks so much to Dr. Barbara Ma for sharing how she's working to push forward this paradigm-shifting treatment for melanoma and other solid tumor cancers. I'm Erin Welsh. Advances in Care is a production of NewYork-Presbyterian Hospital. As a reminder, the views shared on this podcast solely reflect the expertise and experience of our guests. To listen to more episodes of Advances in Care, be sure to follow and subscribe on Apple Podcasts, Spotify, or wherever you get your podcasts. And to learn more about the latest medical innovations from the pioneering physicians at NewYork-Presbyterian, go to nyp.org/advances. [outro music]
