Tumor Infiltrating Lymphocyte Data Signal Promise for New Options to Treat Advanced Melanoma

Ryan Sullivan, MD

Tumor infiltrating lymphocyte (TIL) therapy is an immune-oncology (IO) strategy that has been studied for over 2 decades in advanced melanoma, according to Ryan J. Sullivan, MD. Until recently, data around TILs have not been comparable with IO therapies already approved for the treatment of melanoma.

In prior research conducted by the National Cancer Institute (NCI), good responses were achieved in patients who were able to receive TILs. The reality, however, was that most patients with advanced disease and poor prognosis did not survive long enough for the TIL growing and harvesting process to reach completion.

“Without a way of delivering these quicker and without a way of having multiple centers involved in clinical trials, the respectability of the data was going to be in question. The data was never great, it was just like, is it reproducible across multicenter trials or across groups of patients that can't make it to Bethesda to be treated at the NCI,” Sullivan, associate professor, Medicine, Harvard Medical School and associate professor, Hematology/Oncology, Massachusetts General Hospital, told Targeted Oncology™, in an interview.

At the 2022 European Society of Medical Oncology (ESMO) Congress, research from the Netherlands showed that good and durable response were attainable using a homegrown TIL product which could be administered at multiple centers. More patients in the study could derive benefit from TILs because they were no required to travel far distances for treatment, according to Sullivan.

An agent that appears to be making TIL therapy a possibility for patients with melanoma in the United States is the autologous TIL therapy, lifileucel (LN-144). Data presented in a poster at the Society for Immunotherapy of Cancer (SITC) Annual Meeting showed that lifileucel achieved a clinical meaningful response rate with response durability.¹

In 153 patients with advanced melanoma from cohorts 2 and 4 of the C-144-01 trial (NCT02360579), the objective response rate was 31% at a median follow-up of 36.5 months. Notably, 42% of patients who responded to lifileucel had responses lasting for more than 2 years.

In the interview, Sullivan, discussed the history of TIL therapy, how new data may lead to future approved TIL agents, and other ways TILs may be used in advanced melanoma.

TARGETED ONCOLOGY: Can you discuss prior research of tumor infiltrating lymphocytes in melanoma? What safety/efficacy was shown with this strategy?

Sullivan: The history of tumor infiltrating lymphocyte therapy or TIL goes back to the late 80s and early 90s. In a develop therapeutic strategy from the National Cancer Institute, there are a lot of iterations on this, but ultimately it involved a tumor harvest isolation, growing up at the TILs, and then patients would come back be lymphodepleted, given the TIL and then given high dose IL-2. Then, we would see how it worked. In the historical datasets from the National Cancer Institute, and then subsequently other centers, response rates tended to range in the 20% to the high 50%. There was always a lot of excitement about it, but also a lot of concern. Were these response rates seen because they were highly selected patients who had to get on a flight, go to the National Cancer Institute for a consult, and then go home and then come back and get TIL harvested, then go home and grow the TIL. Then, once it was sure they could grow the TIL, which took 6 or so weeks, patients would come back and get the therapy. Patients who had rapidly progressing disease would never make it long enough to get TIL harvested. Without a way of delivering these quicker and without a way of having multiple centers involved in clinical trials, the respectability of the data was going to be in question. The data was never great, it was just like, is it reproducible, across multicenter trials or across sort of groups of patients that can't make it into Bethesda.

In recent years, lifileucel was developed to be a centralized processing center, but having multiple centers seeing patients. TIL would be harvested at multiple places and then the products would be sent to a centralized place, grown, and then given back to patients at the centers where the rest happened. Many centers that could be involved in patients didn't have to travel as far and you might get a better representation of patients. These data may be more believable as a strategy to be rolled out to the to the field at large.

At SITC this year, results from the INV-COM-202 were presented. Can you talk about the findings from the melanoma cohort?

The initial data with lifileucel was encouraging. The trial that was presented at SITC was a merging of 2 cohorts. For cohort 2, which included post PD-1 treated patients, I think the other piece is that with the emergence of immune checkpoint inhibitors in melanoma and TIL, we have better tools.

This strategy of TIL was not thought of as something that would need to be done initially, but would be in the setting of an unmet need, of not knowing what to do for patients who have progressed after anti-PD-1-based therapy and anti-CTLA4-based therapy. It was thought that this might be a good time in a patient's treatment journey to offer this type of therapy.

The initial cohort is to answer the question, does this strategy work for patients who have received PD-1 therapy and possibly PD-1 and anti-CTLA4 therapy in our needs of additional treatment? Cohort 2 data looks good. Relatively speaking, the response rate of 35% is amazing. For the post PD-1 setting, we hadn't seen response rates like that with any other therapies other than BRAF targeted therapy. More importantly, what we've seen from that cohort was an impressive durability of response.

In the old days of the NCI, the only durable responses that happened were the complete responses, which might have been 20% of all responses. What we're seeing here is that it didn't have to have a complete response to be durable. Whether it is something about the biology of PD-1-based therapies, we're setting up the tumors to have TIL and going to be associated with more durable responses. Maybe that was part of it. Maybe another part of it is that the growing time was less. You might have a more stem-like TIL population instead of a more exhausted TIL-like population. It's not entirely clear. From what we're seeing from cohort 2, at least a third of patients are responding and most of the responses were durable. With the kind of time beyond response, lasting 2,3,4 years, cohort 4 was very similar. Post PD-1 patients have a little bit worse disease and bulkier disease and more disease sites that are more likely to have an elevated LDH. The response rate was a little lower, it was upper 20s, but those responses still tend to be durable. When you combine the 2 data sets, you get a treatment that still is associated with response about a third of the time, and response are durable.

I think the takeaway from this dataset is that TIL is an option for post PD-1-resistant patients and is an option that not only can lead to responses some of the time, but can lead to durable responses. It offers another potential way to induce a durable immunologic response in patients with melanoma.

Perhaps placing it also into context, there was a theory trial presented at ESMO this year by a group at the Netherlands Cancer Institute. The study randomized patients to a homegrown TIL. The regimen very similar to lifileucel, but it wasn't the same centralized lifileucel production of the TIL. The response rates are quite high. More importantly, this trial randomized patients receive TIL vs receiving ipilimumab [Yervoy]. The patients who received TIL did better than ipilimumab, which would be a reasonable control for patients who have received anti-PD-1 in the frontline. It's not a perfect control, but the trial was launched close to a decade ago, so it would be nice.

How do you think TILs will impact can the melanoma space?

I think it will make an impact in a few ways. I think, firstly, it's very possible that lifileucel will get approved by the FDA based on this data. If they do, then it'll directly shape the field because it'll become a commercial option for our patients and be available so that patients won't have to go on a clinical trial. The immediate availability of something like this for our patients would be huge, it would add another thing that that we can offer to our patients.

What other possibilities could there be for TIL therapy in the future of melanoma treatment?

Looking ahead, having a therapy that's totally a different type of therapy than what we have available offers a lot of potential. One next step may be combining it with the things we already have. It may be combined with anti PD-1, anti-PD-1 plus anti CTLA4, or anti-PD-1 and LAG3. It may also be explored in earlier lines of therapy or in the refractory space.

There's some data with other compounds that suggested that combining these types of drugs with a novel immunotherapy could be useful, even if patients had previously been treated with an anti-PD-1-based regimen. I think that's the second thing, that there may be combinations of therapies that currently are being studied, and it potentially could be a next step beyond just having TIL. The other thing is that there are a lot of ways of modifying and manipulating cells. If you’re getting a TIL harvest from a patient, it's entirely possible that there are ways to make those TIL better. You could select for tumor antigen specific T cells. You can select or treat those cells in a way to make them a better TIL. There's data that's been generated from a lot of labs in this space trying to come up with a better way of not necessarily giving TIL, but a better product that they can generate just by doing certain modifications after the TIL is harvested and before patients receive the TIL.

Another way of doing that is to modify what they're giving it with. They may be able to give less chemotherapy or give it with different cytokines. Instead of giving high-dose IL-2, there's a lot of modified IL-2 therapy that might be useful in this setting. I think having proof to the field that this can lead to approval usually generates more investment, not just in the pharmaceutical industry, but also in the academic centers. People will begin to study this more and try and sort out new ways of modifying the cells. I think the field will change because there will be a product that we can give to patients post PD-1 as a new treatment option. The field will change because it enables us to better study combinations of known therapies, approved therapies, or experimental therapies that might make the TIL therapy better. Then, it also has the potential for modifications of the T cells before they go in to make them better.

_REFERENCES:

_{1. Iovance Biotherapeutics announces updated clinical data for lifileucel in advanced melanoma at Society for Immunotherapy of Cancer (SITC) Annual Meeting. News release. Iovance Biotherapeutics. November 10, 2022. Accessed November 16, 2022. https://bit.ly/3UJW2M0}