New Cell Therapies May Hold Key to Treatment of Advanced and Rare Skin Cancers

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined again by Dr. Brian Gastman, medical and surgical director of Cleveland Clinic Cancer Center's Melanoma and High Risk Skin Cancer Program. He previously joined us to discuss Merkel cell carcinoma, and that episode is still available for you to listen to. He's here today to talk to us about new cell therapies that may hold a key to treatment of advance and rare skin cancer. Welcome Brian.

Brian Gastman, MD: Thank you, Dale. Appreciate it.

Dale Shepard, MD, PhD: Maybe you can remind us again about your role here at Cleveland Clinic.

Brian Gastman, MD: Sure. My background has been involved initially in surgical removal of high risk cancers, heavily focused on skin, but also some sarcomas. You and I deal with those together, as well as head and neck cancer. I've had a long standing interest in research, specifically around tumor immunology, which has dovetailed well with the many recent advancements in immune-based therapies, which are curing patients that were, until recently, incurable. Part of my role has transitioned into helping lead our clinical trials aspects to bring the newer therapies to our patients that will hopefully eventually become standard of care so that we can continue to see advances not just in treatment options, but treatment cures as well.

Dale Shepard, MD, PhD: I like it. Let's talk about some of those now. There's a wide range of people who may be listening and maybe have some familiarity with immunotherapies, but we're going to be talking about cell therapies. Let's start off in ... What is a cell therapy?

Brian Gastman, MD: When you think of most therapies that we give to patients, these are off the shelf products, usually chemically made in a lab. They can be chemotherapies, which are basically toxic agents, and they can be immune therapies, for example, which either block immune signals that normally block immune signals. A negative times a negative is a positive. That's one of the immune therapies. The other type of immune therapy are direct boosters over immune therapies. Many of those are still emerging. They haven't been yet approved. Most of what we have right now, under the topic in standard of care therapy, of immune therapy, are things that block, something that blocks a signal and thus, ultimately, is a positive immune signal. Now, what difference from them in cellular therapies is that these secondarily affect your immune cells, which are cellular therapy inside of your body. Then we hope that those cells will then create an anti-tumor response and cure the patient.

Well, the question is, can we get directly to the target? Instead of giving a therapy to affect the cells in your body to kill the tumor, can we take the cells and either take them out of the patient and give them back to the patient even better than they were, or give them other patients cells to kill the tumor? Now you're getting a little bit closer to the action, so to speak. That's sort of the nuts and bolts, if you will, high level of view of what SILO therapy is. I know we're going to get into some details in a moment.

Dale Shepard, MD, PhD: Yep. Let's go ahead and jump into an example. One of the first example we're going to talk about is tumor infiltrating lymphocytes. What exactly is a tumor infiltrating lymphocyte, and how are we using those for cancer therapies?

Brian Gastman, MD: As a surgeon, this is very special to me because a surgeon who's still practicing in his eighties, Steve Rosenberg at the NCI, National Cancer Institute, realized, like many in the field, that our bodies have many types of immune cells, most of which have nothing to do with a cancer patient's cancer immunity, meaning there's a lot of immunology in a patient with cancer that has nothing to do with their cancer. When we try to treat them, we're have to deal with the fact there's a lot of extra stuff in the patient. His question is, how could I get to the best part of that patient's immune system? Of course, it makes sense that that best part of their immune system might actually be in the tumor. It may not be working as well as we want, but it was in the tumor itself.

In the tumor, tumor infiltrating means went in lymphocytes, and the type of immune cells he was focusing on are mainly CD4 and CD8 type of immune cells, which can kill the tumor. Those are also called lymphocytes, so tumor infiltrating lymphocytes. The idea is you cut out a piece of tumor, you then dissolve the tumor into its parts, tumors have tumor. They have blood vessels and other cells. They also have the choicest, if you will, immune cells that are there, on purpose, to go after the tumor. It's just the tumor is more powerful. What happens is now that you've taken it out of the patient, let's say you get a million of those out. Not all of them are very effective, but some of them are. You then can take that million and expand them outside of the patient to billions.

They also realize, over time, that when they just gave it back to the patient, because of all that extra immunology that's in the patient, it was sort of buggering up the system. They would first lymph node deplete the patient, get rid of their immune system. Temporarily. There are ways of doing it for a short course, like we do for bone marrow transplant, and then pump them with their own cells now expanded thousands of times more. Since they're specific for the tumor, guess where all those cells rush to? They rushed to the tumor. At the time, when they were doing it, they were taking patients who had mainly ineffectual multiple rounds of chemotherapy. They were pretty sick. Their body's have been riddled with the effects of chemotherapy, and still around one in five patients had major responses. In fact, there are patients today who are grandparents, who are alive because of treatment done in the early eighties, because of Dr. Rosenberg.

The other problem, though, it was a herculean effort, requiring millions upon millions of dollars per patient. It really could be recapitulated outside of our National Cancer Institute. What's happening more recently is both emissions, but even more so in industry, people are coming up with ways to make it cheaper, simpler, or faster, so that more patients can get exposed to these therapies. More over, we're combining them with the other immunotherapies to see better effects. We're bringing these therapies to patients before they've seen multiple rounds of, for example, chemotherapies, or even immunotherapies, that were in effectual. Ultimately, the hope is, we're going to see even better benefits than we've been seeing for years, and now you can get it, the hope is, at any local hospital. That's the ultimate goal. That's the basics of TIL therapy, but of course, once industry gets their fingers on it, what TIL therapy was will mutate, so to speak, into bigger, better, faster options for patients.

Dale Shepard, MD, PhD: You mentioned something a bit about response rates in 20%, what would you consider with the newer approaches? What kind of response rates are we seeing? We know that the chemotherapies, and you're on fifth line therapy, you're not going to get a whole lot of benefit. What are we seeing with these?

Brian Gastman, MD: So melanoma, because it's one of those cancers that has a fair amount of immunology in the tumor. When you have a lot of immunology in the tumor, we call that a hot tumor. When you have very little immunology, we call it a cold tumor, or desert tumor. A lot of those "desert tumors" don't do very well with any immune based therapy. They are still relegated to chemotherapy. Unfortunately, may of those are also some of the most deadly cancers, like pancreatic of cancer and sarcoma, but amongst the hotter tumors, like melanoma, what we've seen, especially since we don't give much chemo anymore, is an even higher rate of responses pushing around 40%. Yet those are patients that have still failed at least two or three lines of therapies, most likely. We expect, as we introduce this therapy into earlier lines of treatment, that these numbers will only go up. Usually if you get a response, they're usually pretty meaningful. It's not like you, "Oh, you get a couple months of life." These are much more likely to cure people type responses. It's very exciting. Again, these are patients that are failing all the other good therapies we've already had. Unfortunately, in these particular patients, it didn't work.

Dale Shepard, MD, PhD: That was another question I was going to pose, is about durability of response. Typically, it's not very long with chemotherapy, things like the immune checkpoint inhibitors. There is a percentage of people who have very, very long responses, even cures, similar with these agents, or along about the same lines of immunotherapies?

Brian Gastman, MD: Even more so. In fact, the patients are "cured," get complete responses, or at least, complete response based on, let's say, a metabolic imaging type response. They're usually more likely to die of a different cancer, or different problem, than this cancer. We know that because if you go, there are many patient who've had multi-decade, I think after a couple decades, you can call that cured, situations. The question is how many patients can we get there? Not everybody who gets a response are going to get that kind of meaningful response. But if you do get that kind of meaningful response, it is usually long lasting, if not permanent.

Dale Shepard, MD, PhD: You were talking about TIL therapies and it sounds still a little on the cumbersome side to get at this point, and how it's given, but tell me a little bit about side effects. Everyone listening has an impression of side effects of chemo. How is this different?

Brian Gastman, MD: Sure. One of the biggest concerns with the therapy isn't the actual therapy, it's the run-in into the therapy. We have to do what's called lymph node depletion, as I mentioned earlier. You've got to essentially remove most of the immunology of that patient so they can't fight even a cold, kind of immunology. They're getting rid of all those lymphocytes. That happens temporarily over, depending on the protocol, five to seven days. During that sweet spot, where they don't have much other immunology, we not only give them the TIL therapy, we also give them what's called interleukin tube. It's one of those signals that directly augments the immune system, but has a lot of side effects. It's in that period of time where we can see what's called cytokine storm and the other type of very high immunologic side effects that can hopefully not be deadly, but certainly make a patient very sick.

That limits who can get these therapies. It's similar, again, to bone marrow transplant situation. There are patients, if you're older, if you're performance status is low, that we can't give to. The other issue, it's not so much a side effect, is the amount of time to produce and manufacture the therapy. Imagine you're going to get the drug, but you can't get it for a couple months. You got to go through surgery. You got to wait for the drug to be produced offsite. They have to do quality checks, and then you got to get everything set up so you can come in and get that lymph node depletion.

During that time, there's a risk that your tumor can get out of control, and again, you will not even be able to get it, or even worse, unfortunately. In terms of long term side effects from TIL therapy, it's similar to immunotherapy, but it's less likely to cause general auto immunity because again, these immune cells are more specific for your tumor. But if they're going to cause auto immunity, will be things that we see in the tumor itself. For example, in melanoma, you have a lot of melanocytes. Melanocytes give you your pigmentation. Alopecia, loss of pigmentation is possible, but in terms of the colitis, pneumonitis, that we see with other agnostic immunotherapies, it's less so. It's really that early component where we see the major side effects. They can be significant.

Dale Shepard, MD, PhD: We've talked about tumor infiltrating lymphocytes, or TIL therapies. What about natural killer cells? What's the role of natural killer cells?

Brian Gastman, MD: Some of the therapies that were, we call solo therapies, were born out of solid tumor oncology. TIL therapy could be one of them because solid tumors have a place to infiltrate into, unlike liquid tumors. Others have been born out of what we call liquid tumors. NK cells has been more along those lines. The advantage of NK cells over a TILs are, is that because TILs are going after what's called antigen, which the way antigens are, they're proteins in our cells that are presented on the outside of the cells in a way that not only tell the body about the cell they're attacking, but also where that cell came from. It's the same way the body knows if you transplant a liver, that even though I recognize those proteins, but those aren't from my body, I better go attack that liver. That's why you need transplant medication.

Those are antigen specific therapies. NK cells work differently. Their receptor engages a ... It does not require any antigen specificity like TILs do. Thus, you can literally create NK cells from a different patient and give them to a different patient. Thus, it's much more readily available for patients. There's not as much lead in. You don't have to do lymph node depletion, or if you do, it's less so. The problem is, so far, at least in solid tumor, unlike liquid tumors, which I would call lymphomas and leukemia under that umbrella, it hasn't been as effective. At least certainly in what we've seen. It may be because the target response is not as powerful when you're dealing with a protein that's not only a protein of interest that you want to go after, but a protein of interest that's from your own body. But that's what NK cells are. It could be just a challenge that we need to figure out how to get more out of. Meaning, it is probably something there, there, but we haven't really unlocked the full promise of NK cells, but again, there's hope and rationale to use them, especially since you don't have to do all the things you have to do, like we just mentioned in TIL therapy.

Dale Shepard, MD, PhD: You mentioned certainly using IL2 with TIL therapy combinations, combining these sort of immune cellular therapies with traditional chemo. Are there things that are currently ongoing that look particularly promising in terms combinations?

Brian Gastman, MD: Yeah. Well, one of them, for example, is patients who either have, or have not seen our best immunotherapy, which is PD1 or PDL1 inhibition, who went on have TIL therapy. Once the TIL therapy ends, because it's an event, not really a process, they then go on anti-PD1 therapy. Although these are sort of smaller earlier phase trials, the data is very encouraging. It looks better than TIL therapy alone. Now, it could be because these patients are being treated a little bit earlier in their disease course. They haven't failed as many therapies, but regardless, it does point to the idea that something like TIL therapy may be pushing to earlier and earlier, even first line, eventually, therapy, and then you can then give them all the other therapies that are available to them now.

The big use of chemo, for example, lung cancer, is for that run-in, meaning I have to wait two months from my therapy. I don't want my patient to, God forbid, become untreatable anymore, or even die. What am I going to do between now and then? I think people are looking at options in that regard. The other thing is, is that I mentioned high dose IL2, but there's a lot of other cytokines out there that have been manipulated, that may give you the same kick to the immune system without all the side effects. That's under exploration today, but any immunotherapy that's being done in any combination will be looked at in combination, as well, with various cellular therapies. That's why we always say there's more trials than our patients.

Dale Shepard, MD, PhD: Are there any other types of immune cells that you see as being particularly promising to be developed in the future?

Brian Gastman, MD: Well, the two big ones, really, are transgenic T-cell receptor therapies, as well as what's called CAR-T therapy. Let me start with the first one. I told you earlier that the TIL therapy, we make tens of thousands of times the number of cells a patient would've made themselves, hoping that we'll find the right TIL, if you will, and that one expanded, just like all the other ones that didn't matter as much. That key one is the one that will end up killing the tumor. But what if I can make the T-cell receptor, the receptor on those cells, even more powerful? Engineer them to be specific again, something that maybe your body couldn't make on its own, or couldn't make as powerful? Companies are investing heavily in that. In addition, there's something called CAR-T cell therapy. Whereas, a TIL, or an engineered TCR, T-cell receptor, recognizes process proteins that are made specifically for that patient as an antigen on the outside of the cell, basically like a flag saying, "Don't kill me, or kill me." That's what the flag is for.

Imagine, though, I could create something that doesn't care about that. It just looks for a protein that's sticking out the end of a bad cancer cell. The tumor cancer hide behind what we call selfness, meaning all of our cancer cells come from our normal cells. The difference between a cancer cell and a normal cell, sometimes isn't enough for our bodies of immunology to tell that the difference. But if that cancer cell is a lot of a particular protein and I could create something on an immune cell that recognizes the full protein, and then that triggers a signal in that cell that then rev up and kill the cancer cell, that's sort of what a CAR-T is. The bottom line is, it causes a very powerful signal and turns those cells on to kill whatever it recognizes. Those are also very powerful.

That, again, was sort of born out of liquid tumors. It is the standard of care for multiple liquid tumors, especially CD19 lymphomas and leukemia, depending on which type. Different line can be first line and second line, et cetera. Again, the question though is, will we ever find a protein that is so differentiating that we can kill the tumor in the solid tumor space like we did in the liquid tumor. In the liquid tumor, we don't care if it kills the normal and the cancer cells. We can live with that. But in the solid world, we can't do that, because for example, we don't want to lose all your skin, or your heart, or something like that. That's what they're working on, but I think those are emerging and you will see those the next five years, in solid tumors, like melanoma, and a higher skin cancer.

Dale Shepard, MD, PhD: What would you consider the biggest gaps to success? Is it the availability of ... You mentioned more trials than patients. Is there ability to study it? Is it complications with the treatment, delivery of treatment? What do you think are the biggest gaps to moving forward at this point?

Brian Gastman, MD: Sometimes, with industry, when you have a hammer, everything's a nail. Shat I mean by that is, if you have a TIL therapy and it's working, you're going to put all your effort into that one pathway. It's great. It's bringing therapies that weren't available to patients where they live, but it's not expansive enough. Meaning there needs to be more research to try to figure out why they work sometimes, and why they work sometimes really well and not really as well. I think, in there, we'll unlock how we make the, for example, TIL therapy, more powerful and more ubiquitously anti-tumor, or curable. I think that's really the big issue, is how do we tailor these therapies per patient? There are companies focusing in on it, but the companies that are first in line, if you will, are sort of using the more general agnostic approach, just enhance all the TILs, like they've been doing for decades. The next generation, or maybe the generation even after that, of TIL and solo therapies, will be more patients specific, make more tumor specific. I think we'll be seeing much greater effects, and we may even shift again in how we treat our patients. We may even move away from standard immunotherapy as much as we went to it so recently.

Dale Shepard, MD, PhD: Very good. Well, Brian, you've had some great insight for us today and I appreciate all your efforts in this space. It looks like it's truly going to be a type of therapy that'll help our patients.

Brian Gastman, MD: Yeah, I just one last thing I should mention though, IOVANCE, which is sort of first in line, their major trials are done. They're actually not waiting to get TIL therapy through trial mechanisms. They're waiting for their FDA approval to actually make it insurable, billable process. In theory, you could have it done anywhere. The next companies are trying to figure out what we can do that's different than them, but very soon, likely, in probably second quarter 2022, in theory, any hospital with the right setup can give this to their patients without having a clinical trial. It's really exciting. It's been 40 years in the making.

Dale Shepard, MD, PhD: Very good. Well, thank you very much.

Brian Gastman, MD: All right. Thank you. I always appreciate to be on this.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting ClevelandClinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, ClevelandClinic.org/CancerAdvancesPodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. Don't forget, you can access real time updates from Cleveland Clinic's cancer center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.