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Melanoma TIL Therapy
My Insights on the Latest Data on Tumor-Infiltrating Lymphocytes in Melanoma and Clinical Applications of TIL Therapy

Released: February 14, 2023

Expiration: February 13, 2025

Allison Betof Warner
Allison Betof Warner, MD, PhD
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Key Takeaways
  • Tumor-infiltrating lymphocyte (TIL) therapy involves the harvest and ex vivo expansion of naturally occurring antitumor cells for infusion back into the patient.
  • Recent clinical trials have demonstrated promising efficacy and durable responses with TIL therapy for patients with advanced melanoma after progression on anti‒PD-1 therapy.
  • Patient selection is important when considering TIL therapy.

There is currently no standard of care for patients with refractory melanoma after progression on anti‒PD‑1 based therapy. Treatment options include chemotherapy or interleukin (IL)‑2, or ipilimumab plus nivolumab combination therapy for patients previously treated with monotherapy or nivolumab plus relatlimab, but enrollment on a clinical trial is the best option for these patients. One of the most promising areas of clinical trial research for patients in this setting is adoptive cell transfer using tumor-infiltrating lymphocytes (TILs), a new application of immunotherapy first developed in the late 1980s at the National Cancer Institute. TIL therapy has been brought into the mainstream by recent breakthroughs in the ability to reliably produce TILs, freeze and thaw them to allow transport, and reduce production time. Briefly, TILs are harvested from a surgically resected tumor, expanded ex vivo, frozen, and returned to the oncology center. Patients undergo a nonmyeloablative, lymphodepletion regimen before receiving an infusion of expanded TILs, which is then followed by a series of high-dose IL‑2 treatments.

The Latest Evidence on TIL Therapy in Melanoma

Very impressive data concerning TIL therapy in melanoma has been reported within the past year. First, cohorts 2 and 4 of the phase II C144‑01 trial examining the TIL therapy lifileucel in patients previously treated with ≥1 lines of therapy including an anti‒PD-1 therapy reported an overall response rate of 31%, with almost 80% of patients seeing a reduction in tumor burden. Of importance, more than one half of the responses were still durable at 1 year after this 1‑time treatment. The durability of response off therapy represents the real promise of TIL therapy and has led to a lot of excitement because no other treatment option provides this possibility for patients who have progressed after anti‒PD‑1 treatment.

Similarly, impressive data from the phase III M‑14 TIL trial were presented by John Haanen, MD, PhD, and are now published. This phase III trial compared therapy with TILs produced at the Netherlands Cancer Institute vs ipilimumab in patients who had progressed on ≤1 previous lines of therapy, most having progressed on previous anti‒PD‑1 therapy. The primary outcome, progression-free survival, was significantly improved for patients treated with TILs vs those treated with ipilimumab. The rate of adverse events (AEs) was high and concentrated in the first 14 days post treatment but were manageable. The AEs were as expected from lymphodepletion and IL‑2 treatment, including febrile neutropenia and thrombocytopenia, presumably resulting from lymphodepletion and fevers, rigors, hypotension, and renal toxicity associated with IL-2. Of importance, recent data indicate that the number of IL-2 doses does not correlate with response to TIL therapy for patients who discontinued because of AEs, meaning it is not necessary to continue IL-2 treatment if AEs such as hypotension or end organ dysfunction occur, potentially making this a much more tolerable treatment for patients and safer to deliver.

TIL Therapy in the Evolving Melanoma Treatment Landscape

Many oncologists are excited about the potential use of TIL therapy in the second line or immediately after progression on an anti‒PD‑1‒based regimen if TIL therapy receives regulatory approval, as is anticipated. Data from the M‑14 trial indicates that TILs may be superior to ipilimumab alone, and it is possible that TILs would be more effective than ipilimumab based combination regimens. TIL therapy is a very potent treatment, requiring good performance status, so it is key to treat patients while they are still in good health—ideally, as early as possible post progression on anti‒PD‑1‒based therapy. Although noting concerns about cross-trial comparisons, the contrast between the M-14 and C‑144‑01 data (where the median previous lines of treatment was >3) suggests that TIL therapy in the second line may produce better outcomes than treating patients in later lines of therapy.

Considerations for Patient Selection

Patient selection for TIL therapy requires several important considerations. First, patients need to have resectable disease. Time to treatment is also a concern. Manufacturing TILs requires 16-21 days after tumor resection and 5 days of lymphodepletion are performed before TIL infusion, meaning that patients are not receiving active treatment for their melanoma for some time. Thus, TILs may not be the ideal therapy for patients who have swiftly progressing disease and are rapidly declining. It may be possible to bridge with a short course of immunotherapy or targeted therapy to slow tumor growth before pursuing TIL therapy, but this is not always effective or practical. Other eligibility factors for TIL therapy include good performance status and normal renal function to be able to tolerate lymphodepleting chemotherapy and IL-2. Age is a relative consideration, as most patients treated to date with TILs have been younger than 70 years of age, although patients older than 70 years with excellent performance status have also been treated, and this older patient population will likely be further explored as candidates for TIL therapy.  

The Future of TIL Therapy Is Bright

I believe TIL and other cellular therapies hold a lot of promise for melanoma and other solid tumors. There is an ongoing trial exploring the combination of immune checkpoint blockade with TIL therapy in earlier lines of therapy (NCT03645928). TIL therapy may even have potential as a frontline or neoadjuvant therapy, which is being examined in upcoming trials. I foresee expansion of TIL therapy similar to that seen with checkpoint blockade, which was initially approved in melanoma and then in multiple other cancer types, bringing the treatment benefit to larger groups of patients. Some success has already been seen with TILs in both non‑small-cell lung cancer, head and neck cancer, and cervical cancer, and I think there is much more to come.

Important considerations as we move forward will be the ability to treat patients in an outpatient setting, which would be game-changing. This would depend on modifying the intensity of the lymphodepletion regimen and providing alternative formulations of IL‑2 or other cytokines to avoid the requirement for inpatient monitoring and high levels of care. Finally, TIL products might be genetically modified with different T‑cell receptor stimulatory domains or to produce their own cytokines. I believe the future will demonstrate a great potential for next-generation TIL products.

An in-depth text module with downloadable slides on TIL therapy in melanoma will be available here soon.

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