Oncology

Melanoma

Advertisment

Tumor-Infiltrating Lymphocyte Therapies: Current Strategies and Future Directions

conference reporter by Elizabeth I. Buchbinder, MD
Overview

At the 2024 ASCO Annual Meeting, researchers presented data from several studies investigating the potential of tumor-infiltrating lymphocyte (TIL) therapies in the treatment of unresectable or metastatic melanoma.

 

Following these proceedings, featured expert Elizabeth I. Buchbinder, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Buchbinder’s clinical perspectives on these findings are presented here.

“. . . while TILs are very exciting, this therapy is not for every patient. There is still a lot of work to be done to improve the risk-benefit profile of TIL therapy to make it safe for every patient and to reduce the time needed for production so that patients with rapidly progressive melanoma and other tumors can receive it.”
— Elizabeth I. Buchbinder, MD

Adoptive cell therapy with TILs reflects investigative efforts that have been ongoing for some time. Work on TILs from National Institutes of Health (NIH) dates back to the 1980s, and some of the work originating in that space with high-dose IL-2 actually set the stage for related areas in the field of immunotherapy today. At that time, the difficulty with TIL therapy was that it was very intensive and could only be done at the NIH and, over time, at a few other centers.

 

Even today, for a patient to undergo TIL therapy, part of their tumor must be removed, and the T cells (ie, the lymphocytes) within the tumor are isolated from the tumor, grown in a lab, and fed, which still takes some time. Patients then receive lymphodepleting chemotherapy, followed by an infusion of the isolated immune cells and then some sort of boost to those immune cells, typically IL-2, to make them more potent so that they destroy tumor cells from the melanoma elsewhere in the body.

 

A recent development that led to the commercialization of TIL therapy is a process by which a central lab receives the tumor, produces the TILs, and then sends them back out to treatment centers. Data from the C-144-01 study (NCT02360579) with lifileucel looked very good in a highly pretreated melanoma patient population, with durable responses in the 30% to 40% range based on the different cohorts being treated. As a result, the US Food and Drug Administration (FDA) granted accelerated approval to lifileucel for the treatment of unresectable or metastatic melanoma that was previously treated with a PD-1–blocking antibody and, in BRAF V600–positive disease, a BRAF inhibitor with or without an MEK inhibitor. This therapy is starting to be used all over the country.

 

There are many other efforts involving TILs across the world in other centers with similar commercial links, and other TILs are being developed through academic and private cell therapy labs, so there is quite a bit of work going on in the TIL space.

 

Some of the exciting things that we saw at ASCO 2024 with regard to TILs included efforts to modify the TILs in pursuit of a variety of goals. One such goal is the reduction of toxicity from IL-2. Toxicities that stem from IL-2 include hypotension, fevers, chills, third spacing/edema, and kidney and liver dysfunction. In abstract 9515, Amaria et al presented preliminary phase 1 data on OBX-115, which is a very interesting TIL because it is engineered to be IL-2 sparing. One does not have to give the IL-2 because the TILs express membrane-bound IL-15 when exposed to acetazolamide, supporting TIL expansion and persistence.

 

There is also work being done to see whether TILs might be given earlier in the treatment sequence for advanced melanoma. At ASCO 2024, we saw the presentation of the frontline trial of TIL therapy in combination with pembrolizumab (abstract 9505). The study showed some very nice responses, with the caveat that there was a death in that group of 23 patients (ie, 1 patient had a grade 5 treatment-emergent adverse event due to sepsis). More data will be needed before this becomes a standard approach.

 

Lymphodepleting chemotherapy (ie, usually cyclophosphamide and fludarabine) is a source of acute toxicity with TIL therapy with thrombocytopenia, lymphopenia, and anemia, and so, infection is a major concern with these patients and is a potential cause of mortality. I think that thrombocytopenia, in particular, is an issue in melanoma if you have a patient with brain metastases. Those tumors are particularly prone to bleeding already, so, as a result, issues with bleeding in the brain can be seen with lymphodepleting chemotherapy.

 

The time that is needed to manufacture TILs is also an area of concern. There is a period of weeks that is required to make the cellular product (ie, for culturing and expansion). Since melanoma is a tumor that can progress quickly, this length of time led to questions being raised at the ASCO conference by several investigators who were wondering about patient selection in TIL trials, that is, if there were many patients who were screened for TILs or had TIL harvests but were never able to receive TILs because their cancer grew too quickly and whether those patients should be included in the outcomes analysis. By only including patients who received TILs, would there be a selection bias for less aggressive disease or a population of patients with slower-growing tumors that might respond more favorably to TIL treatment?

 

On the one hand, the more that needs to be done in the lab to modify or engineer TILs, the longer it can take between surgery and infusion. However, there are many different ongoing efforts and various interesting approaches aimed at improving TILs as a therapeutic strategy. For example, some of the TCR approaches are very exciting, and many of these different directions that are being taken right now might shape where the field will go with TILs in the future.

 

To summarize, I would say that, while TILs are very exciting, this therapy is not for every patient. There is still a lot of work to be done to improve the risk-benefit profile of TIL therapy to make it safe for every patient and to reduce the time needed for production so that patients with rapidly progressive melanoma and other tumors can receive it.

References

Amaria RN, McQuade JL, Davies MA, et al. OBX-115, an interleukin 2 (IL2)-sparing engineered tumor-infiltrating lymphocyte (TIL) cell therapy, in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma [abstract 9515]. Abstract presented at: 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.

 

Betof Warner A, Hamid O, Komanduri K, et al. Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. J Immunother Cancer. 2024;12(2):e008735. doi:10.1136/jitc-2023-008735

 

Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10(12):e005755. doi:10.1136/jitc-2022-005755

 

ClinicalTrials.gov. Study of lifileucel (LN-144), autologous tumor infiltrating lymphocytes, in the treatment of patients with metastatic melanoma (LN-144). Updated July 12, 2023. Accessed June 14, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT02360579

 

Haanen J, Los C, Phan GQ, Betof Warner A. Adoptive cell therapy for solid tumors: current status in melanoma and next-generation therapies. Am Soc Clin Oncol Educ Book. 2024;44(3):e431608. doi:10.1200/EDBK_431608

 

Morotti M, Grimm AJ, Hope HC, et al. PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function. Nature. 2024;629(8011):426-434. doi:10.1038/s41586-024-07352-w

 

Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233(4770):1318-1321. doi:10.1126/science.3489291

 

Sarnaik A, Lewis K, Kluger H, et al. Lifileucel TIL cell monotherapy in patients with advanced melanoma after progression on immune checkpoint inhibitors (ICI) and targeted therapy: pooled analysis of consecutive cohorts (C-144-01 study) [abstract 789]. Abstract presented at: Society for Immunotherapy of Cancer 37th Annual Meeting; November 8-12, 2022; Boston, MA.

 

Thomas SS, Gogas H, Hong YK, et al. Efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, and pembrolizumab in patients with immune checkpoint inhibitor-naive unresectable or metastatic melanoma: updated results from IOV-COM-202 cohort 1A [abstract 9505]. Abstract presented at: 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.

 

US Food and Drug Administration. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. February 16, 2024. Accessed June 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma

 

 

This information is brought to you by Engage Health Media and is not sponsored, endorsed, or accredited by the American Society of Clinical Oncology.

Elizabeth I. Buchbinder, MD

    Senior Physician and Medical Oncologist
    Melanoma Treatment Center
    Dana-Farber Cancer Institute
    Assistant Professor of Medicine
    Harvard Medical School
    Boston, MA
Advertisment