Episode 282: TIL Therapy and Melanoma With Dan Olson

Chadi sits down with Dr. Daniel Olson to discuss the growing excitement surrounding tumor-infiltrating lymphocyte (TIL) therapy in melanoma, including how these personalized cellular therapies are created (and sometimes engineered in the lab), the logistical challenges of collection and reinfusion, and the clinical data that led to FDA approval based on a single-arm study. Dr. Olson also explores treatment sequencing with immunotherapy and targeted therapy, the severity and duration of associated toxicities, response rates seen in practice, and the expanding potential for TIL therapy in other malignancies such as lung and cervical cancers, offering a practical and forward-looking look at one of the most promising advances in solid tumor oncology.

Check out Chadi’s website for all Healthcare Unfiltered episodes and other content. https://www.chadinabhan.com/

Watch all Healthcare Unfiltered episodes on YouTube. https://www.youtube.com/channel/UCjiJPTpIJdIiukcq0UaMFsA

Transcript

SPEAKER_00 0:12

Jaddy Nabhan and it's Healthcare Unfiltered. Thank you for tuning in to this episode of Healthcare Unfiltered on the sixth season of this podcast. We are in year number six. I'm very grateful for you tuning in, subscribing, and always providing feedback about Healthcare Unfiltered. And folks, if you haven't heard about Healthcare Unfiltered Express, please check it out. It's a shorter format of Healthcare Unfiltered where you can actually this when we discuss uh relevant areas, relevant topics, clinical trials in a very short format, about 10 to 12 minutes. And you can listen on that to that, and you can watch it on all formats uh on all channels as well. Today's podcast is with Dr. Dan Olson. Dan Olson is an assistant professor of medicine at the University of Chicago, and he has significant interest in immunotherapy and as well as melanoma. And today's podcast, we are gonna talk about TIL therapy, tumor infiltrating lymphocyte therapy. There's a lot of buzz about this, and I think it is timely to understand what about TIL therapy. Um, just you know, large principles and how it applies today and what's new down the pike. Uh and by the way, folks, before I air the podcast episode, I just want to uh share with you uh what I have learned about a company called Premium. Premium, you can go to premium.co. It's actually a secure web-based platform where um folks in the community and hematology oncology fellows can get second opinions from thought leaders across all disciplines and across all disciplines in oncology. You can actually have a particular account, and if you have any type of question, you immediately can message any of the key opinion leaders and you get an answer within 24 to 48 hours. What I like about this, frankly, is that you can actually get outside of your geographic area and you can actually get information, get opinions from folks who are not within your vicinity, also from folks that you probably wouldn't have known otherwise. It's also secure, there's no PHI. I just uh got a chance to uh know about these folks, and I thought I would share that with you. And especially when we talk about these topics, complicated topics, still therapy, CARTI, and other elements, it's always helpful to get opinions from uh your peers and people that you trust the most. So check it out and always drop a line and let me know what you think. And before the air of the episode, I taped with Dr. Dan Olson. Um, want to plug both of my books, Toxic Exposure, The True Story Behind the Monsanto Trials and The Search for Justice, and The Cancer Journey, Understanding, Diagnosis, Treatment, Recovery, and Prevention. Both books are available everywhere. And guess what? It is these books, uh, the The Cancer Journey is going to be translated to Portuguese, it's going to be translated to Polish and to Lithuanian, and it's also available everywhere in Europe. So please check it out. Okay, folks, Dr. Dan Olson on Healthcare Unfiltered, Talking Till Therapy and Beyond. Healthcare Unfiltered, we've got the first timer from the University of Chicago, my alma mater, Dr. Dan Olson. Welcome to the show. Thank you for having me.

SPEAKER_01 3:29

Pleasure to be here.

SPEAKER_00 3:30

So, Dan, a bit about you. Uh, let's know a little bit about you and what you do, and um tell us a bit about um the scope of practice and research that you're involved in.

SPEAKER_01 3:42

Yeah, so primarily my primary identity is really as a melanoma oncologist. So clinical researchers spend um two full days in clinics, seeing patients, and then um wear a few different hats in terms of you know what I'm doing, doing in terms of research. So um, you know, I work a lot on cancer immunotherapy, have a lot of interest in that through learning through melanoma, um, you know, helped uh publish a trial and treat patients for PD1 refractory melanoma, and that tends to be what we see in clinic as a referral center. And um, frankly, melanoma treatments are getting more complicated and more um logistically complex. And so we tend to get more referrals for those patients who are getting uh, you know, referred after progressing non-standard therapies in the community. So um I do a lot with that with cell therapy, um, also with cell therapy in general for solid tumors. That's kind of a new and exciting thing and something we're um really interested in at University of Chicago, and that overlaps a lot with melanoma because the first um cell therapy solid tumor approval is for melanoma with litholucellar till therapy. So um definitely involved with that, also with some of our early phase trials. Um, and I also see patients with sarcoma. Um, not as much research with that, but um something I do. But honestly, the majority of my research is really in the immunotherapy space, those clinical trials, and especially cell therapy.

SPEAKER_00 4:59

Well, I'm really excited to have you then because um I actually asked you to come on the show to talk about a topic that I personally find it complex, and I'm a medical oncologist. So I assume a lot of my viewers and listeners probably share the same. We want to talk a bit about till therapy. We're gonna try to simplify it, understand it a little bit better, and understand a bit more of its applications and and what's going on as a form of cellular therapy. And and I also want to talk a bit about what's new in the treatment of uh melanoma. But let's start with um let's start with till therapy. We've been hearing a lot about this over the past couple of years. Can you simplify it for us?

SPEAKER_01 5:44

Yeah, it's uh it's a it's a complex process in therapy, but certainly I can try and break it down. Um it has a really you know amazing and kind of rich history. It's been around for a long time, but it's only really become um relevant in terms of patient treatment since the approval, which was in February of 2024. So still relatively new, but it's its prior history goes back to the National Cancer Institute, where it was developed, you know, starting even conceptually in the 80s and through the 90s by Steve Rosenberg and his lab at the surgery branch of the NCI, um, where they made some of the foundational discoveries for studying T cells outside the body. It was necessary to, you know, discover IL2 before that so that you could even activate and grow T cells outside the body. But over time, through some of their foundational discoveries, they realized that you can actually extract T cells from tumors and then um leverage those to turn them into a cell therapy product. Um, so conceptually, what tills are tumor infiltrating lymphocytes, um, people are probably familiar with that term as like a prognostic biomarker. Like people talk about it for you know, breast cancer or other cancers, where if you find a lot of T cells in the tumor, it's prognostically a favorable thing. With melanoma, it's a therapy. So we're taking those T cells we find in the tumor, many of which, if you look at them, some of them will have specificity for tumor antigen. So, you know, there's sometimes a lot of T cells in a tumor. There's more in melanoma because it's an immunogenic or hot tumor. Um, you know, we think about a lot of the uh, you know, UV-induced DNA damage in the tumor, the high mutational burden, the quality of the angens, a lot of reasons melanoma is a hot, the sort of prototypical hot tumor. There happen to be a lot of T cells in that. And so that means that taking those T cells to turn into a therapy is likely to be more successful just because the number of the T cells is higher. And that's what's some you know somewhat different about melanoma is compared to other epithelial cancers, colon cancer, breast cancer, or others, where yes, there are some tills, but they're hard to leverage those for th for a therapy. So that's the the sort of foundational background on you know why melanoma is the prototype.

SPEAKER_00 7:47

So because there are so many of there's abundance of T cells.

SPEAKER_01 7:51

Yeah. So if you tried to take make tills from just colon cancer, breast cancer, um there wouldn't be as many of them. It's been tried, it hasn't been as effective. And so with melanoma, you can literally take the population of T cells you find, expand them in the lab, and then a portion of those cells are going to be tumor reactive and therapeutic. Um, whereas with other cancer types, if you put them through the same process, you won't get enough tumor-specific T cells for them to be effective. And that's been tried and unfortunately not successful.

SPEAKER_00 8:21

Is the idea that kind of um it's the idea that the T cells in the melanoma are defective, they're not doing their job. So I'm gonna take them to the lab, engineer them. Um, what am I actually doing? Like with CAR T, we kind of know what we're doing with CAR T. What are we doing in the lab when we when it comes to T tilts?

SPEAKER_01 8:41

Yeah, so really we're just um expanding the number of the T cells and then activating them. So um it's technically a form of engineering, but uh don't overinterpret that to mean that we're engineering like the this the receptor specificity. So like with a CAR T cell or a TCR T cell, you actually are kind of picking the antigen and putting the receptor in with TIL, it's agnostic of what the antigens are. And so we're we just know that by proximity, those T cells that are in the tumor, some of them are going to be reactive against melanoma antigens. Um, what's interesting in some of the work they've done at the NCI is that when you look at what antigens, like in patients who are responding to TIL, if you sequence the T cell receptors and find the antigens, um, you find that they're personal antigens in most cases, meaning that they're personalized to the patient. Um, there are some shared antigens for melanoma, but the majority are truly personal antigens. And so when we go through this process of expanding and activating those T cells, um, we don't really know what the targets are. Um, we just know from experience that, you know, some percentage of those T cells are going to react against the melanoma. Another percentage of those T cells are like viral reactive or just bystander cells, but we're not smart enough or, you know, we don't have the technology to separate out right now the truly tumor reactive ones from the bystander cells. So we expand the full pool and give that to the patient as the treatment.

SPEAKER_00 10:02

And so so that's actually key for listeners. So I mean, in CART, you're kind of really working on the receptor, the specificity between the receptor and the antigen. And here, all what you're doing is you're expanding T cells and hoping that by having more number of T cells. And how are we expanding them in the lab? Like what do we actually do to expand them?

SPEAKER_01 10:23

Yeah, so it's a really interesting manufacturing process. So um the way it starts is you identify a patient who's got tumor of a sufficient size to actually, you know, create the therapy. So it's typically a tumor that's over two centimeters in size, not necrotic. Um, and a surgeon will excise that. We uh they sort of trim it in the OR, they put it um in media and they send it out the door, and it goes to the manufacturing facility for the sponsor who makes till or lifeleucil, which is iAvance. And they um they have a big manufacturing facility where they essentially um take different pieces of the tumor. Um, all of the exact details of how that's done, I don't know for sure, but in the general concept is they select different parts of the tumor and then in different wells, and essentially uh through a process of expansion through feeder cells that generate a lot of cytokines that promote T cell activation, division, expansion, they grow over the course of weeks. Um, and then you know, from there, they essentially will test it to see um how many cells they have, make sure it meets the sort of cutoffs for an in-spec product or you know, meets the right number of um cells. And they do some other testing on it that's um, I think happened in discussion with the FDA. We don't know the full details of it, but in general, are looking at different functional markers to make sure it's a what we think is likely to be an active T cell product, and then it's cryo-preserved and sent back. And then at that point, we can do the treatment part of the tills.

SPEAKER_00 11:50

How long is this process? And I ask because with CAR T, a lot of times we say one of the biggest logistical issues is the time it takes from collections until reinfusion. What are we talking about here?

SPEAKER_01 12:02

It's a long time. So the brain to vein time, as we call it. So when you think, you know, you meet a patient who's got refractory melanoma and you want to treat them, it's gonna take almost two months. So um till is even more complicated than CAR T in terms of the manufacturing because you have the surgery component to it. You know, with CAR T, you can you go through aphoresis, and that's a pretty reliable and um, you know, straightforward procedure. With surgery, there's some complexity to that depending on where you're getting the tumor, but then also um scheduling OR time, which is sometimes not as easy as aphoresis time. So, you know, you're looking at a couple weeks to meet the surgeon, get the OR time scheduled, get the insurance approval. And then once the tumor is out the door, um, you can expect it to come back in about five weeks. That's the manufacturing timeline. Um, so it ends up being a while, and that's you know important because you have to factor that into the treatment and your sort of expectations with patients. And sometimes, you know, refractory melanoma is not an easy disease. And sometimes you're dealing with tumors that are growing faster than you know what the timelines allow. And so you try and do everything you can. Sometimes you have to get bridging therapy. Um, sometimes you have to try and acknowledge that it may not come back in time. And that's you know, that's obviously brutal, but you know, it's it's a tough disease, and there's not a lot of other great options out there. So it's some sometimes part of what you have to do. But anyway, that timeline you build into it to expectations.

SPEAKER_00 13:22

Are there chances where you don't get a viable product back?

SPEAKER_01 13:27

Yes, that can happen. Um so you know, it's not an off-the-shelf drug. It's something that you actually have to manufacture, and there's really complex biology that's intrinsic in this. Um and so there are certain things that have been published so far that, you know, let us know what are the things that we can control that would increase the likelihood of getting a viable product. Um, but there are some things that are out of our control that we really don't know. Like, do prior treatments influence the population of T cells that would then be used for product? Or, you know, so there's things like that that are harder to control. But the things that we do understand, for example, is that you know, taking tumor from lymph node is likely to be uh inspect product, whereas, you know, visceral uh sites of disease like liver, just lung, um, you may have a higher risk that the product may not meet the specification. So in general, it doesn't happen for that many patients, um, but it is something that happens with enough frequency that you definitely have to think about it. And um, if you have a choice of where to get tumor from, we know some sites are better than others, and you're gonna choose the ones that are higher probability.

SPEAKER_00 14:30

What like what's percent of product failure you think in your experience?

SPEAKER_01 14:34

You see, you'll see it quoted anywhere from 10 to 20 percent. Um, and in the early days when we were starting this, we were probably you know higher than that because it was interesting when the trials were done for tills, um, you only needed a billion cells to be in spec. But after it went through the review through the FDA and everything, there's a set of criteria that are needed to release the product and be in spec. And you actually need to have a higher cell count. It needs to be over seven and a half billion cells. And so when we started out for commercial till, we were kind of operating on the guidelines that were done in the trials for you know the amount of tumor to submit. Um, and so it was a more problematic then, but now we typically submit more tumor, um, try to be more aggressive with the procurement, and that's increased the the inspect rate. And then this knowledge that you know lymph nodes tend to be better, um, that's helped us as well. So it's uh it does happen sometimes, but it's you know, probably in that 10 to 20 percent range is more likely.

SPEAKER_00 15:30

And you mentioned, obviously, in melanoma that because it's a kind of highly immune type of a disease, uh, that's why it was the perfect prototype for till therapy. What other cancers till therapy is being explored for?

SPEAKER_01 15:45

Yeah, so it tends to be other immunogenic or hot cancers that, you know, have a pretty um high abundance of antigens and therefore, you know, good um starting material with tills. So um there's data out there for activity of tills in lung cancer. Um, so there's been a single arm study where there's you know a pretty reasonable response rate in refractory lung cancer, somewhere between 25 to 30 percent. Um, there's also a study in cervical cancer, which you know has a lot of HPV-related proteins, leads to a lot of T cell recognition of those oncoproteins. And so um you can definitely generate tills from cervical cancer. Um, the data on that is not back yet. There's some posters and things presented that you know show reasonable response rates in refractory cervical cancer, but um we don't know if those are things going to be approved. The real um, you know, next that's and that's for what we call bulk till, like what we're doing for melanoma, where you you just take the T cells and manufacture them. There's a whole other level of what's coming for engineered tills where you're actually doing other things like engineering cytokines into the T cells or using CRISPR to knock in or knock out different proteins to make the T cells function differently. So those hold promise for treating other cancer types, but right now it's really based on this kind of hot, cold tumor. Really, only the hottest tumors are the ones that you can generate tills from. Melanoma is really the prototype for that. So that's where we are with this first approval. But there's definitely more coming.

SPEAKER_00 17:07

So let's shift a little bit on the treatment though. How are you positioning that therapy? Um is till therapy for melanoma right now is kind of like your last resort type of thing?

SPEAKER_01 17:19

Well, good question. So it kind of is viewed like that because it is such a big deal to do it. And I think, you know, to think about how you frame it, it's it's good to think about too like what's the treatment look like? Because it's not the easiest treatment to give. Like it's hard. Um, you know, you you have to go through that whole surgery manufacturing. But then when you actually treat patients, you do a three-step process of L lympodepleting chemo, similar to what we do for CAR T, but a heavier dose. So this the myelosuppression is actually worse. It's harder. And then we infuse the T cells after seven days of conditioning chemo. The T cells they use are autologous T cells. They're not, they don't cause a lot of like cytokine release or anything like an engineered or CAR T would. Um, but then the real kicker is that we have to chase it with IL2. So high dose IL2 we give for up to six doses after the infusion of the T cells. Hydose IL2, which you know, some people might remember from the early 2000s and 90s.

SPEAKER_00 18:11

I do, I'm I do, and it's that's not I I've actually treated patients with high dose IL2, and I don't want to ever treat them again with a high dose IL2.

SPEAKER_01 18:19

Yeah, well, it's back in vogue now because we give it as a you know supplement to the till. It's not the same, it's not multiple cycles, but it's still a high dose. And so we you have to manage those toxicities again. And so as you might remember, that's not an easy therapy. Um, so that's the challenge with um with giving it is that you have to, you know, make sure your patient can get through that, you know, and that in the context of having bad melanoma is not always the easiest thing. So um it is a hard treatment. And so what's really different about it is that the the treatment toxicities are very high. You get a lot of you know, neutropenia, the chemo toxicities, you get the IL2 toxicity, fevers, chills, hypotension, all that, but it's temporary. So IL2 is a very short half-life. They're in the hospital for a couple weeks, you get them through it, it's very hard in the moment. Most patients say that's the worst thing I've gone through, but then it's done and they're getting better within a few weeks, and you're done at that point. So good to know that because it is really hard to do. And so um, it's not knowing that, you know, it's not something we want to leave until the very last minute because it's something that gets harder to give the further a patient goes along in their treatment. Um, and on top of that, we have data to suggest that tills work better the sooner you give them. So, you know, really the indication for tills is on label, it's after PD1 failure. And if a patient has a BRAF mutation, it's after having received BRAF mech therapy. You don't necessarily have to be refractory to it. So if a patient's, you know, not responding to frontline melanoma treatment, we want to be talking to TIL about them early, given all the complexity that goes into it, knowing that it works better if we give it earlier. We don't want to be given this third, fourth, fifth line because it's gonna be much harder to do and it's probably not gonna work as well.

SPEAKER_00 19:55

Yeah. What's the response rate when you do that? Like what's the approval was based on response rate, survival? How did that happen? Like, what's the yeah?

SPEAKER_01 20:04

So it was approved on basically a single arm study where there was a couple different cohorts that were pulled together. Um, so hundreds of patients, you know, response rate I think was around 31%, um, but a very durable response rate. The median hadn't been reached at that point. So um it's a fraction of patients, it's not the majority. Um, so that was what granted its approval. And then we know a fraction of those patients are going to get durable responses, about 25% five-year overall survival. So um, you know, that's much better than what we had before because melanoma was a really bad disease if you didn't respond to standard treatments, but um, it's still not, it's not, it's not like first-line checkpoint inhibitors, for example. It still has its challenges. So um our experience is is on in line with that. There was also another randomized study of TILS that was done in Europe, and it was done exclusively in the second line setting. So a lot of people who progressed after adjuvant therapy and got PD1 monotherapy, and it was randomized against uh CTLA4 antibody, and the response rate there was 50%. So, used in an earlier line of therapy, the response rate was superior. And they've shown other data that if you give that same European till product after multiple more prior lines of therapy, the response rate goes down a lot and is really in line with what we see saw in uh the Ivanse trial. So um, all that argues is that you know giving it earlier tends to work better. It is a therapy that can be a home run, it's an immunotherapy response patients we think can be cured. So um we wanna we want to get it in while we can, is what I'd say.

SPEAKER_00 21:35

Let's say we're from here to treating melanoma. This is obviously more of, like you said, some people say it last resort, but you uh uh nicely said that you're starting to look at a bit earlier in the course of the disease. Um let's talk about treating melanoma in view of all of this. In metastatic disease for patients with melanoma, um, things have changed a lot. Uh Obviously, but uh how how how do you structurally organize this in an easy way for us to understand? Because there's obviously the targeted thing and the when you do NGS and what you find, and there's the IO, which is not necessarily NGS-based, and all of these things. So more of a like a how do you approach the treatment of melanoma given how many options you have today?

SPEAKER_01 22:27

Yeah. So if we if we focus on the stage four, the metastatic patients, um, you know, we've got a handful of things in the toolbox, and the big distinguisher is if you have a BRAF mutation, so that's about 50% of patients. So um, you know, the only real choice how you start therapy is if you're BRAF mutated, do you use BRAF inhibitors or targeted therapy or do you immunotherapy? Um, and there was a you know a cooperative group randomized phase three study that did targeted therapy versus um PD1 CTLA for combo immunotherapy. Um, and there's a survival benefit with immunotherapy first. So pretty much the sequence question is answered. Um, everyone, you know, most patients should be getting immunotherapy first. Um, and if you have a BRAF mutation, you save the BRAF inhibitors for later. Um, then the real question is, you know, we've got a few different immune checkpoint inhibitors we can use, like how do you pick which ones to use first? So we've got, you know, the PD1 antibodies, we've got a PD1 like free combination called Opdulag, and then we've got um Ipilimit MAB and the volume map, so the PD1 CTLA4 combo. And with each one of those, the response rate goes up, but the toxicity also goes up. And so, you know, a lot of people will use the big gun first, which is IP NIVO, where you get you know 50 to 60 percent response rate that's typically durable, um, but the toxicity, high grade toxicity rate is the same amount, 50%. Whereas if you use obdulag or you know, PD1 monotherapy, response rates are in the 30 to 40, sometimes a little higher with obdual ag, but um the toxicity is significantly lower. So essentially, if you're giving it, we're gonna give immunotherapy first. You look at your patient and say, how many, how many shots on goal do you think I'm gonna get? Um, do I want to use the big gun with IPNEVO first? Because I might only have one shot. So use it first in those high risk situations. Otherwise, you sequence your therapy typically with you know, monotherapy, obdual ag and then give IP NEVO. Um, there is a debate about you know when to use targeted therapy. So BREF inhibitors, they work great, high response rates, but um the duration of benefit is not always long. Most patients progress, and when you progress after targeted therapy, you tend to progress pretty aggressively. And so it can be hard to get people to subsequent therapies after that. So I think the, you know, in general, most people will use targeted therapy second or third line. Um most patients with melanoma are treated in the community with checkpoint inhibitors and targeted therapies, and that's the right thing to do. I think, you know, in my world, I'm seeing these other new immune therapies come up, and we know that using immune therapies after BREF inhibitors is very challenging. And so I typically try to use the therapies that can generate a long-term remission or cure the immune therapies before I go to a targeted therapy. But that's our sequence. It's you know, immune therapy, targeted therapy for those patients, and then TILS, and then you know, some of the other newer things that are coming out will factor in in the future.

SPEAKER_00 25:10

And and I I I was gonna ask about that. It's becoming a, I mean, is it becoming difficult to do clinical trials in melanoma given the fact that you have, I mean, you're essentially you know, picking a clone of the disease that has failed target therapy, immunotherapy, and possibly till right now. So, what other drugs in stage four disease that coming down the pike that at least piqued your interest? And and I really it's I don't know how you would design a trial for stage four disease right now. Like the the it has to be like a phase two study against whatever. Uh yeah. I don't know.

SPEAKER_01 25:48

There's um, yeah, there are some interesting therapies out there for sure. So I think the ways to approve them is to say, you know, um combine them in the first line with a checkpoint inhibitor, which tends to be the backbone of so many studies because it it's a relatively tolerable drug. Um and you know, we have very good expectations of what that is. And so if you were to say checkpoint inhibitor plus XYZ novel therapy versus you know, investigator's choice standard checkpoint inhibitor, if you can beat that, that's a way to um, you know, bring a drug to first-line melanoma. And then the other place would be, you know, in later lines of therapy. So after PD1 antibodies, which is the major checkpoint inhibitor uh andor targeted therapy, you know, then we would have a randomized study of an investigational therapy versus investigator's choice. Um, so I think that would, those would be the places where we would study it. And there are therapies that are coming up. Um, the big news is that recently there was this drug that we thought was going to be a proof for melanoma. It's called RP1. It's an oncolytic virus that you actually inject into the tumors and it was given with an involumab. And they had a single arm study showing a response trait in the 30% range. Um, but they actually got a FDA review letter and they uh it was denied. Their BLA didn't go through. And so we were all thinking it might go through, but it it didn't. So I think there's been a change in the criteria for later lines of melanoma at the FDA, and the the standards are tougher. So um I think to your question to how do we get a drug approved, I think it probably has to be a randomized study after uh, you know, standard therapies don't work. So it would be something investigational versus, you know, investigators' choice of other checkpoint inhibitors and things like that. And there is a really important study coming up, which is um a TCR T cell study. So it's a um it's another cell therapy, um, but unlike a CAR T cell, it's an engineered cell therapy where the receptor is a T cell receptor and not a chimeric antigen receptor, because T cell receptors can see intracellular proteins presented on HLA molecules, whereas CARS can only see surface molecules. So a lot of these cancer-specific proteins and melanoma are intracellular. And so you have to use a T cell receptor to see it. And there's a phase one study from this company called AMADIX, it's a German company showing over a 50% response rate in refractory melanoma, melanoma subtypes that don't respond well, like mucosal and uvial melanoma. It looks like a really potent therapy. So there is gonna be a randomized study of this drug, IMA203 versus investigators' choice of any later line of therapy, including TIL. So that's gonna be a really interesting study. Um, there also are some very interesting bi-specifics that use T cell receptors that are going into frontline. Um, so it's gonna be one of those drugs plus a checkpoint inhibitor versus other checkpoint inhibitors, and those look very interesting. So um there's a lot happening to melanoma. There's very exciting cell therapies, there's interesting bi-specifics, um, there's a triplet checkpoint inhibitor like PD1 LAC3 CTLA4. So there's a lot going on.

SPEAKER_00 28:48

So my last question to you about melanoma is um does the choice of what you do in the adjuvant setting affect what you're gonna do in metastatic disease in terms of what you do first line, second line? And if so, how would you do that?

SPEAKER_01 29:04

Yeah, so typically if a patient, you know, for patients who have stage three disease, we'll oftentimes give an adjuvant checkpoint inhibitor monotherapy, so Pembroke or Nivo. And if you progress on that, um, certainly we would want to offer a different type of therapy afterwards, like retreating with a checkpoint inhibitor, you know, if you progress pretty quickly after that or on it is not going to work very well. So we would give um, you know, a PD1, C TLA4 combination, which has about a 30% durable response rate. Um, certainly if you're BRAF wild type, we could be thinking about till at that point. Um, you know, whether to give that before, after C PD1, C TLA4 combos is an open debate, but I think earlier is better with that, in my opinion. Um and then, you know, some patients would get targeted therapy, you know, depending on where you're being treated and what options you have. So, yes, we kind of move through our treatments at that point. And I think if you progressed on adjuvant therapy, we would move to our other tools in the toolbox to see if we can get things under control.

SPEAKER_00 30:00

Well, that's amazing. I mean, I think uh are there new targets that uh that are happening in melanoma that uh are of interest, uh particular angens or targets that peak in your interest?

SPEAKER_01 30:13

Yeah, so the big one is um called praying, which is uh it's what it's in a family of antigens we call cancer testis antigens or embryological proteins. So these are um proteins that are part of our normal DNA, but they're usually methylated during adulthood and not really expressed. But then in oncogenesis, a lot of these um genes become unmethylated and expressed as tumor-specific proteins. So prame is one that's um highly expressed in melanoma. And it's kind of it's expressed regardless of like the you know, hot, cold tumor paradigm. It's you know, it's not something that's a neoantigen, it's a, or in the traditional sense, it's more, you know, something that's unmethylated and expressed. And so it's expressed in, you know, cold melanomas like melanoma of the eye or mucosal melanomas. And so um, it means that if you can engineer a T cell receptor to target that, you can, you know, bring good anti-tumor activity to melanomas that wouldn't respond to checkpoint inhibitors. So it's really something additive to checkpoint inhibitors, and that's a really exciting target. There's the again, I mentioned these bi-specifics that are targeting that, and then these TCR T cell therapies that are also targeting Prame. So I think that's a really interesting target. I think there are you know two registrational trials um ongoing for it. So I think that's gonna be really important for melanoma. It's also interesting to say that Prame is you know not a melanoma-specific protein. It's highly expressed in endometrial cancer, it's in ovarian cancer. Um, so it's gonna be interesting to see if that you know pans out into other tumor types as well.

SPEAKER_00 31:43

Dan, did I forget asking you anything you think our viewers or listeners would be interested in?

SPEAKER_01 31:49

Uh I think you know, it's hard to go through the till talk without thinking about what's next. And as I mentioned, TCRT cells are really exciting, but also engineered tills are very exciting. So there's two main ones that I think are super interesting. Um one is what we call cytokine engineered tills. So um there's been some early data presented that you can actually engineer in a cytokine receptor to a till to where it essentially auto-stimulates so you don't have to give the IL-2 therapy, which is the toxic part of the treatment. Um, and it tends to make, we think, make the tills work better, but it also makes them grow faster. So you don't need as much starting material. So you actually could grow a T cell or till product at a core needle biopsies, um, and you could give it without having to give IL-2. Essentially, it has a IL-15 receptor in it. And there's been some early data showing that to be really exciting. So I think that's something that's really intriguing because IL-2 is a major drawback of till therapy in terms of how many people we can treat with it because of its toxicities. And when we think about giving tills to patients with lung cancer, with you know other diseases where there's comorbidities and we don't want to give IL-2, having a product like that that has you know a less intense toxicity profile means that this could be a therapy that that you know extends to other tumor types beyond melanoma. One, it could work better in melanoma, but it could work in lung cancer, cervical cancer, or others. So that's really exciting. And then the other really exciting thing in the till world is this idea of antigen-selected till. So, as I mentioned, we don't try and pick out the tumor reactive T cells, but there actually is a process for doing that that's been pioneered at the NCI, where you essentially predict what you think the neoantigens in the tumor are. You take those tills out of the tumor and you co-culture those together with those antigens present, synthesized, and then you can identify the tumor reactive T cells and essentially find the needle in a haystack till and pull those out and preferentially expand them. And that's really exciting because it means that you can find those rare tumor reactive T cells in colon cancer, breast cancer, you know, the cold tumors, but still get something like till to work for it. So it's complicated, it's logistically, you know, really complex. Um, but it there's some early data from the NCI that's really exciting. It's in trials. I I hope it works logistically and you know, obviously mechanistically, but um, it's just really cool. So I gotta say, that's something that I'm really excited about.

SPEAKER_00 34:10

It's fascinating. It's like not all T cells are created equal, right? Like let's select the T cells that really matter. Yeah. Dan Olson, thank you so much for coming on Healthcare Unfiltered. I really appreciate the time. And uh, this was really a lot of fun knowing about TIL and how it affects melanoma therapy. Thank you. My pleasure. Okay, thank you so much, Dan. Thank you for joining in everyone. I really appreciate your support. I appreciate you letting me know about this podcast and what your thoughts are. Thank you for telling us about Till Therapy. This is really important and very, very good to know. I hope you all enjoyed this podcast episode. So don't forget to subscribe, rate this podcast, share it with your friends and colleagues. Don't forget what we talked about in terms of second opinion platform with premium.co. It's an excellent company that you should get to know. And I'm curious your thoughts. Easy to communicate, message thought leaders across all disciplines of cancer and get their opinions about timely topics at the point of care pertaining to things you're doing every single day. And before I let you go, I'm gonna leave you with a saying by Isaac Newton. Plato is my friend, Aristotle is my friend, but my greatest friend is truth. Until next time, take care of