Tumor-Infiltrating Lymphocyte (TIL) Therapy

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a Medical Oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and Co-Director of the Cleveland Clinic Sarcoma Program. Today I'm happy to be joined by Dr. Thach-Giao Truong, Director of the Melanoma Program here at Cleveland Clinic. She's here today to talk to us about TIL therapy. So welcome.

Thach-Giao Truong, MD: Hi, Dale. Thank you for having me.

Dale Shepard, MD, PhD: Absolutely. Give us a little bit of an idea, what do you do here at Cleveland Clinic?

Thach-Giao Truong, MD: I'm the Melanoma Program Medical Director. I oversee the melanoma care for the enterprise, and work collaboratively with other multidisciplinary team members.

Dale Shepard, MD, PhD: Excellent. So we are going to talk about something called TIL therapy. We have a lot of different people might be listening in, and they're scratching their head like, "What in the world is that?" So what is TIL therapy? Just start there.

Thach-Giao Truong, MD: Yeah. So T-I-L, TIL, stands for Tumor-Infiltrating Lymphocytes. What's really unique about this therapy is that it's a treatment that's made from your own tumor-infiltrating lymphocytes. So it's an autologous, fully personalized therapy that's generated by removing a piece of a patient's tumor, your own tumor let's say, and then these tumor-infiltrating lymphocytes, which are already on your tumor and know your tumor, are identified and propagated in the laboratory in vitro and then re-infused back into you at a much larger volume where they can be more effective.

Dale Shepard, MD, PhD: So by putting those lymphocytes back into one's body, then what happens?

Thach-Giao Truong, MD: They go after the tumor. Because that is a hurdle where we found ourselves. We've had major advances using immune targeted treatments, checkpoint inhibitors are the most well-known, with the first being ipilimumab approved in 2011, where specific checkpoints on how T lymphocytes are engaged, are manipulated so that they're more active. Here we're bypassing specific checkpoints, we're just taking tumor lymphocytes, T cells, that are already known to the tumor and re-infusing them.

This has several advantages. First of all, one reason why checkpoint inhibitors don't work for everyone is that you could activate a T cell, but it may not find your tumor. The other thing that can limit its use, and also its risks, are that you can aberrantly activate these T cells and then generate side effects, like autoimmune side effects. Then last but not least, the checkpoint inhibitor effect may not last as long and it may not be as effective. That's something that we would want to study more, but having your own TIL therapy can improve the outcome by getting past some of these resistance mechanisms.

Dale Shepard, MD, PhD: We know that traditional checkpoint inhibitor therapy, it's approved in so many different kinds of cancers. I'm jealous because I treat sarcoma not necessarily so active. But that being the case, there's certain characteristics of those tumors that are immune reactive, immune sensitive to checkpoint inhibitors. From the biology of these, is it likely that there could be additional tumor types that would be effective?

Thach-Giao Truong, MD: Absolutely. I would love to see it studied in sarcomas for example. In fact, that has been done through other laboratories, and even at the level of therapeutics. There was a company that looked at TCRs and breast cancer. There are tumor-infiltrating lymphocytes across many tumors, breast cancer being another one. If one were able to find a way to stimulate an immune response by utilizing tumor-infiltrating lymphocytes, even for these tumors who have not been as responsive to checkpoint inhibitors, that would be really a paradigm shift for all of us.

Dale Shepard, MD, PhD: I guess in terms of just that infiltration of lymphocytes, I guess with some tumors that just naturally happens, is there a thought that we can do something to make tumors more likely to acquire that lymphocyte infiltration, and might improve the benefit of this kind of treatment?

Thach-Giao Truong, MD: Yes. In fact, this is something that was found after the trials were completed, looking at responders versus non-responders to TIL therapy. Having more TIL generated from your tumor harvest, meaning when the surgeon resects and it's then propagated in lab, those who come are able to generate more T cells subsequently do have a higher response.

Dale Shepard, MD, PhD: When we think about responses, everyone, when they talk about these immunotherapies, particular checkpoint inhibitors, I always get the sense that people think the responses are far greater than they truly are. How do response rates compare to something like a TIL therapy, compared to say a checkpoint inhibitor therapy?

Thach-Giao Truong, MD: So you always have to also think about at which point in their journey the patient sees the treatment. What's remarkable about TIL therapy compared to checkpoint inhibitor combinations, in the setting of resistance to monotherapy, is that TIL therapy is the first approved next line treatment for refractory melanoma where the majority of patients had been ipilimumab exposed. So this is really our most effective checkpoint inhibitor combination to date that's been studied in any tumor type, but especially melanoma with 60 to 80% response rates.

In that refractory setting, with that pre-exposure, TIL therapy was able to generate a 40% response. So compared to other post-PD-I therapies that were studied against just PD-I monotherapy refractories, that's substantially higher. Not, in the frontline setting... This was just shared at ASCO, and this is also data from Dr. Rosenberg's lab who pioneered studying this treatment many years ago and has been evaluating this treatment modality. In frontline when TIL is given, the overall response rate is 60%, so that's substantially higher than PD-1 monotherapy. It's higher than its efficacy in later line, suggesting that even though you are generating the treatment by a tumor harvest, how exhausted those T cells are probably still are very important.

Dale Shepard, MD, PhD: I guess we think about improvements in sort of that upfront response, but it seems like, to my mind, one of the attractions to traditional checkpoint inhibitors, PD-1, PD-L1, is durability. Instead of with chemo, kind of the expectation, you might get a response but it's not going to last long. You have, in many cases, that sort of tale, people that don't really have recurrences, they have very stable disease. Do we have enough long-term data with TIL therapy to know if we get similar durability?

Thach-Giao Truong, MD: It's not been as long as for the checkpoint inhibitors just because it's a more recent therapy. So at this point the median follow-up is getting close to three years, but how well it's doing so far for those who are responding, I would anticipate that it'll end up being very similar to what we're seeing in checkpoint inhibitor therapy. Meaning, if you get a response, it is likely to be durable. For checkpoint inhibitors, we have 8-year data now, and 10 years soon, either later this year or next year, where 80% of people who get a response maintain that. For the 20%, when something comes back, if you re-initiate treatment, it comes back. That we don't know yet, and that's certainly something that I think everyone wants to know. If your tumor progresses after TIL therapy, what are your options?

Dale Shepard, MD, PhD: We've had several episodes we've talked about CAR T therapy. So if we're thinking about these cellular things interacting with the immune system broadly, differences, similarities?

Thach-Giao Truong, MD: Thank you for that thoughtful question. So cell therapy, as a whole, is really an amazing bioengineering feat because, like you're saying, we are generating a treatment that is mimicking our own immune system and then going after our tumors. CAR Ts, it's like a lock and key. You need a target that the T cell recognizes to get it to what it needs to do, this is why it's very popular in heme malignancies where there often is a common target. In solid tumors, the common targets that exist, like HER2, or BRAF, or EGFR, they've just been hard to generate as CAR Ts.

There is one that's been made and being studied for certain breast cancer targets, and there is one also for melanoma that's being developed at City of Hope and UCLA. But you can see, it's always been smaller populations. For example, the IL, R2-L, alpha that UCLA and COH are doing is 10 to 15% of patients. What is amazing about TIL is that it doesn't require a preselection because it belongs to the patient. It does require a processing. You need a surgeon, you need to make the treatment. In that way, CAR T is something pre-made and that you can use when you need it, although now there are more autologous options there as well. But for solid tumors, certainly that has been some of the limitations because it requires the pre-screening to see if it's a fit.

Dale Shepard, MD, PhD: I guess if people aren't really familiar with this as a therapy, very, very practical question, what does the process look like? You kind of described what is involved, but patient shows up in your office, what does logistically that look like? Timeframes? How long would it be until somebody could actually get the treatment once you've made that initial contact?

Thach-Giao Truong, MD: No, that's such a great question, and so unique to this treatment. So when they meet us, you have to find a good site from which you can harvest tumor and do a surgical resection. It has to be in a location that's accessible, so that's one. It needs to be in between 1.5 to 4 centimeters, so there has to be a certain size. If it's too small then it might not generate enough product later. Then the surgery is scheduled. Once the surgery is scheduled, that's where the company actually meets us. So this is a great collaborative effort between physicians and industry to generate a fully personalized treatment for patients. The company actually meets every surgeon in their OR, it's an amazing logistic enterprise.

They take the tumor there, and it takes them about six weeks to make it. This is not dissimilar to other cell therapies that are personalized because it takes time for some to screen, or for some to make a certain product. Then during that time while they wait, some patients have a little tumor elsewhere and so they can wait, or they are on other treatments while they're waiting for the treatment to return. Then an admission is scheduled where they receive chemotherapy to clear their body of any other immune signals that could interfere with this new T cell infusion, we call that lymphodepleting chemotherapy. Then the patient receives the chemo first, and then the product, and then we wait for the cells to recover. We've had people admitted for just a week or two. This was a very young patient with a very healthy bone marrow. On average, people are counseled to expect about four weeks of an admission.

Dale Shepard, MD, PhD: So this is definitely not something that can happen outside of a very specialized center.

Thach-Giao Truong, MD: Correct. Which is why, to start out with, there are 23 early authorized centers, and Cleveland Clinic is one of them. You do need a center that has the capability to generate a cell therapy and administer cell therapy, so an inpatient unit that has experience there, and you need surgeons who have the expertise to do the treatment and coordinate.

Dale Shepard, MD, PhD: You mentioned something about tumor characteristics, one and a half to four centimeter. Is there any way at this point, other than hoping for the best, to select a tumor to be collected, to generate the necessary lymphocytes, like PET scanning or some sort of imaging, or something to say this is going to be a spot that might be high yield?

Thach-Giao Truong, MD: There's been a collective experience and people have been sort of aggregating that over the course of the trial and the early experience now with standard of care. I don't think there's any one particular one-size-fits-all. Usually you always want to have a little bit larger site rather than less. You want a person whose tumor distribution isn't already overwhelming, unless you have a good bridging therapy. The thing that's really life-changing for patients, and we've seen referrals from across the country, is that it's not a treatment where you have to go back and forth every week or every two weeks for two years, which is what our prior treatments were. Here, after that admission, you're then in follow-up. On the trial, the majority of responses were seen early.

Dale Shepard, MD, PhD: I guess something that comes to mind, this is really labor-intensive, certainly must be costly, certainly not something that, at this point, we can give to every patient.

Thach-Giao Truong, MD: Correct.

Dale Shepard, MD, PhD: So what are the factors that go into patient selection? Who's the right patient to get this kind of treatment?

Thach-Giao Truong, MD: The fact that you need lymphodepleting chemotherapy, which is similar to an autologous bone marrow transplant, you do need to have bone marrow reserve. So that keeps us in the eligibility range of a similar population who could tolerate an autologous bone marrow transplant, which are going to be younger people. I think it also has to be someone with a reasonable functional status who could get through such a chemo, and you can't have concurrent infections or severe disease where you can't tolerate that.

The treatment's also given with IL-2, it's not a set dose and it's there to activate the T cells a little bit with a little bit of stimulation to the immune system, let's say. So, as you might remember from the old days where IL-2 was the only treatment we had for melanoma, it can generate some cytokine reactions, inflammatory reactions. So for all those reasons, it is going to be someone more fit with good organ function that we would recommend this for.

Dale Shepard, MD, PhD: So this certainly is an interesting breakthrough in a therapy standpoint. Where's going to be the next break, either with TIL therapies, or what other type of cellular therapy you find most interesting that you're waiting to see what happens?

Thach-Giao Truong, MD: The Friends of Cancer Research recently had a town hall together with the FDA and other regulatory organizations in industry. The major breakthrough of TIL really is that we're able to give something so personalized to the patient that is effective. There are many other mechanisms to deliver cell therapy or cancer therapy, and if we had a way to generate something that's personalized and could be approved, and let's say engineered, let's say with a CRISPR technology, that really would catapult us forward.

Some of those limitations currently are because of how we study treatments. lovance Lifileucel had a long journey to FDA approval to show that they could consistently produce a good product even though it was personalized. So those are some of the challenges we see. But that is our future, we have the tools to do it, artificial intelligence will only enhance the power of some of the data we'll have from that. It's really very exciting, and I'm fully confident that, also for sarcoma, we will have consistent results.

Dale Shepard, MD, PhD: Yes. Well, it's an exciting new therapy. It's complex, but you've explained where we're at and where we can go, and I appreciate you being with us.

Thach-Giao Truong, MD: Thank you very much for having me.

Dale Shepard, MD, PhD: To make a direct online referral to our 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. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.