Autologous TIL Therapy Elicits Durable Responses in PD-1-Treated Metastatic Melanoma

Amod Sarnaik, MD, surgical oncologist in the Department of Cutaneous Oncology, the Immunology Program and the Melanoma Center of Excellence, Moffitt Cancer Center

Amod Sarnaik, MD

Treatment with the cryopreserved autologous tumor-infiltrating lymphocyte (TIL) therapy lifileucel (LN-144) elicited a 38% objective response rate (ORR) in heavily pretreated patients with metastatic melanoma, according to cohort results of a single-arm, phase II trial (NCT02360579).

Cohort 2 of the multicohort trial comprised 66 patients with unresectable metastatic melanoma who received prior treatment with a PD-1 inhibitor (n = 66), a CTLA-4 inhibitor (n = 80), and a BRAF/MEK-inhibitor combination (n = 23). Patients underwent surgical resection for the purpose of TIL generation, and then received 1 week of a cyclophosphamide/fludarabine preconditioning lymphodepletion regimen, followed by a single lifileucel infusion, and then ≤6 doses of interleukin-2 (IL-2).

Additional results, which were presented at the 2019 ASCO Annual Meeting, showed that the 38% ORR comprised a 3% complete response (CR) rate, a 35% partial response (PR) rate, and a 42% stable disease (SD) rate; the disease control rate (DCR) was 80%. At a median follow-up of 8.8 months, the median duration of response was not reached.

In an interview with OncLive, lead study author Amod Sarnaik, MD, surgical oncologist in the Department of Cutaneous Oncology, the Immunology Program and the Melanoma Center of Excellence, Moffitt Cancer Center, discussed the phase II data and how the role of TILs could revolutionize the field of oncology.

OncLive: What was the reason to pursue this type of treatment?

Sarnaik: For the longest time, it’s been known that cancer, especially melanoma, has an acquired larger numbers of mutations, or changes in the DNA, that give patients inflicted with metastatic melanoma the opportunity to have their tumor recognized—that the cancer is being a foreign invader, like a bacteria or virus. In just about any kind of cancer that one can think of, research has shown that the amount of immune cells that infiltrate the tumor is directly proportional to the patients’ chances for survival. Melanoma is one of those cancers with a relatively high burden of mutation that is infiltrated with these immune cells.

Researchers from the National Cancer Institute (NCI) decided to investigate the ability for us to take tumors out of patients and actually grow these immune cells to an extremely high number in the lab, and use that as a form of autologous treatment. They were very successful in doing so, and the treatment has been implemented at other major cancer centers, such as Moffitt Cancer Center.

The purpose of this study is to determine whether there can be a centralized manufacturing strategy, so that patients who live far away from centers, such as the NCI or Moffitt Cancer Center, may be able to get the treatment locally and not travel great distances. Part of the reason for pursing this is to have this adoptive cellular therapy be applied in many different centers in the United States, not just a select few that have a cellular therapy manufacturing facility on site.

The second goal of the research is to determine whether the cellular therapy can still work in patients whose disease has progressed after treatment with the very effective, newer forms of immunotherapy: PD-1 inhibitors. Those are really the two goals of the research: to determine whether a centralized manufacturing strategy can allow cell therapy to be done at a variety of treatment centers in the United States rather than a select few, and then to also determine the treatment may also be effective after frontline PD-1—based therapy.

Could you speak to the unmet need of this patient population?

PD-1 inhibition has revolutionized the treatment of [patients with] melanoma and has also expanded into other cancer subtypes; however, the problem is PD-1 therapy has a 40% ORR. That may go up to 60% when you combine PD-1 with CTLA-4—blocking antibodies, known as ipilimumab (Yervoy). But even then, 40% to 60% of patients will not be able to have a long-term benefit from this form of immunotherapy.

The unmet clinical need involves these patients who are either not able to have demonstrated a durable or long-lasting disease benefit to PD-1—based therapy with or without CTLA-4 inhibition. Or, some patients end up developing adverse events (AEs) from immunotherapy, such that they can’t continue on it. Those patients are very difficult to treat because, as was the case before PD-1 inhibitors was discovered and then implemented, the fallback for these patients are chemotherapy. Other efforts are underway of combining PD-1 with other agents to try to restore disease response after disease progression on PD-1–based therapy, but those efforts haven’t bore fruit. The benefit of this treatment is that it’s an entirely different mechanism of action, and since all of the patients have not been able to be treated with PD-1 inhibitors, we have been seeing some excellent clinical results on this trial.

How is this treatment administered?

As is true with any complex treatment, the first step is to make sure the patients qualify for treatment. Patients have to have metastatic melanoma that is not able to be removed for curative intent by surgery; patients on this particular trial also have to have either progressed on or had some side effects with PD-1 antibody-based therapy. Once they’re determined to be eligible, the local facility will select a metastatic deposit that can be safely removed from the treatment, while still leaving residual treatment against which treatment response may be measured.

The patients undergo surgical resection of at least one deposit of metastatic melanoma, and then that tumor is actually shipped to the central manufacturing facility, where they put the tumor in a series of bioreactors and get their immune cells to grow out of the patient’s tumor. Once the cells have successfully demonstrated growth, the patients are then brought back to make sure that their disease hasn’t gotten worse, as that might be one reason why they won’t be able to have the treatment. But, if the disease hasn’t gotten worse, such that we would think they could tolerate the treatment, the patients then undergo a 1-week course of chemotherapy.

The purpose of the chemotherapy is not to shrink the existing tumor burden; it is to repair the patient’s body to be able to receive the immune cells that were grown from the lab. The reason why the chemotherapy is required has not entirely been worked out, but the thought is that these immune cells need access to cytokines and other growth factors that may be bound up by the patient’s normal circulating immune cells. They get 1 week of nonmyeloablative chemotherapy, but it does not cause permanent damage to the bone marrow.

After the chemotherapy is completed, the patients end up having their cells shipped to the local treatment facility where they are infused into the patient in a central line. They then get up to 6 doses of IL-2; this is a cytokine that promotes the growth of the immune cells that are administrated to the patient. After that, the patient stays in the hospital for about 1 week or 10 days to recover, [we monitor] the bone marrow function, and after that there is no further treatment. The patients are then put on follow-up; one of the benefits of this treatment is that it is a one-time treatment. It doesn’t require several cycles of treatment that is commonly seen with cancer therapies, such as immunotherapy or chemotherapy.

Moving onto the phase II trial presented at the 2019 ASCO Annual Meeting, could you highlight the efficacy and safety data?

This was a single-arm trial, so all patients were planned to receive this TILs adoptive cell therapy. Patients had to be screened to be eligible for the treatment and then, once confirmed to be eligible, we registered 66 patients on the trial. In terms of the patient population, all subjects had progressed on anti—PD-1 therapy. Eighty percent of the patients also progressed on anti–CTLA-4 therapy.

The other class of therapy that’s available for patients with melanoma is targeted therapy with the patients who have activating mutations in the BRAF V600 codon. Of those patients who had those activating mutations, the majority of them had progressed on that as well. These patients were highly treatment refractory. In terms of disease burden, patients had a relatively high disease burden, with 44% of patients having either liver or brain metastases; those patients unfortunately have an extremely poor prognosis. On average, some of their target lesions that were used to determine response were over 10 cm of disease burden.

Because the trial includes nonmyeloablative chemotherapy and IL-2, there were significant side effects seen. While the majority of all patients had a grade 3 or higher AE, most of those were related to the chemotherapy; the chemotherapy suppresses the bone marrow, so there was the expected leukopenia, anemia, and thrombocytopenia, which happened in the majority of patients.

However, out of the 66 patients, there were 2 grade 5 events, one of which most likely related to disease progression versus an AE. One patient died from respiratory failure, but it was not related to the treating investigator’s assessment. One of the benefits in terms of safety of this trial is that of the AEs, the majority of them did occur within 30 days of the treatment. Since it’s a one-time treatment. after 30 days, there were very few AEs experienced by the patient.

If the patients were able to tolerate the chemotherapy, cellular therapy, and IL-2, after [those 30 days] they did extremely well.

In terms of efficacy, of the 66 patients who were treated, we saw a 38% ORR; 25 patients experienced at least a 30% disease shrinkage in the target lesions without any new disease popping up. That included 2 CRs and 23 PRs, but what was also interesting was that 42% of patients had SD, so the DCR in this highly refractory population was 80%. That efficacy is pretty much unmatched when you look at other treatment options that are available for patients who progressed after PD-1—based therapy.

We are interested in trying to determine predictive factors on who may benefit the most from this treatment, and we have spent a lot of time looking at correlative and biomarker data. We have not yet found a specific marker that would be predictive of response for patients. The other thing to think about in this type of treatment is, while it’s good that we have a 38% ORR, how durable are these responses? The majority of the patients who had an initial response are still having a response that is ongoing; 68% of responses have an ongoing response, and several patients are now beyond 1 year in a sustained response.

The dogma that was being propagated in the field is that once a patient progresses on PD-1—based therapy, no immunotherapy can work because you’re selecting for the patients who didn’t benefit from immunotherapy—possibly meaning that their immune system just couldn’t mount an immune response.

These data are very important, because it shows you that in patients whose disease is refractory to PD-1—based therapy, there still is some sort of endogenous immune response and this trial amplifies this by taking the tumor out of the patient and growing the TIL to very high numbers. That, in and of itself, is enough to overcome that resistance to the PD-1 antibody treatment, and what’s even better is we might be able to take these TILs and discover new targets to further activate the TILs and improve efficacy further. We’re happy with the 38% ORR, but we are always greedy in our field and want to do even more for our patients.

Another cohort of this trial is opening soon. Could you discuss the next steps of this study?

This was a cohort that showed that it was feasible to do adoptive cell therapy with TILs in a multicenter trial with centralized manufacturing. The purpose of cohort 4 is to have a blinded independent assessment of disease response in a single-arm study to generate response rates that can be used for FDA registration purposes. For cohort 2, we had the investigators judging the response, and in cohort 4, this is going to be a single-arm registrational cohort that, if the data hold up, should pave the way to FDA approval.

No matter what the cancer is, it turns out the degree of infiltration of the cancer with immune cells correlates with response and outcome, and one of the things that can be done with this technology is it can be applied to other cancers. Melanoma is the low-hanging fruit because the mutational burden is so high, but this can be applied to a variety of other cancers. At the 2019 ASCO Annual Meeting, the similar treatment was being reported for cervical cancer with pretty high response rates. This can also be applied to other cancers that are inherently refractory to PD-1—based therapy, such as pancreatic cancer, and even highly lethal cancers, such as glioblastoma.

The other interesting future direction is if we can come up with strategies to prime patients’ immune cells, so that they get a higher quality of T-cell infiltration, that might also be another avenue to boost responses across all cancer types.

How would you describe the potential TIL therapy has overall in oncology?

The other thing that has been potential for broadening TIL therapy to the field of oncology is further engineering of the TILs in vitro. Right now, the way the TILs are prepared is they are allowed to flow out of the tumor, they are propagated to high numbers, and then given back to the patient in an unmodified fashion. There are efforts ongoing to try to further modify the TILs by genetic engineering, and we have had a lot of improvement in our ability to modify T cells using the CRISPR-Cas9 platform among others, so engineering the TILs may also be an avenue to get a more broad application for TIL therapy for cancer.

Is there anything else you would like to add?

This is a monumental achievement in terms of getting multiple major academic centers—not just in the United States, but this also being now conducted in Europe. It takes a lot of coordination and collaborations. I am proud of our field coming together in order to implement such a relatively complex technology to many different sites, and not just the few sites that have manufacturing facilities on site.

Sarnaik A, Khushalani NI, Chesney JA, et al. Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1. J Clin Oncol. 2019;37 (suppl; abstr 2518). doi: 10.1200/JCO.2019.37.15_suppl.2518.