Ignacio Melero, MD, PhD, Professor of Immunology and Co-Director of the Department of Immunology and Immunotherapy at the Clinica Universidad de Navarra in Spain, was the invited discussant of the M14TIL study. He noted that a 50% relative reduction in the risk of disease progression is impressive in this population, as is attainment of a plateau on the Kaplan-Meier curve; 30% of patients showed long-term stability. Also notable was the 49% response rate, with 20% complete responses, many of which were durable.

“I think there is sufficient information and evidence here to support the standard practice of TIL therapy in incompletely resectable stage III and IV melanoma following anti–PD-1 failure,” Dr. Melero said.

Ignacio Melero, MD, PhD

In contrast to a criticism directed to the early National Cancer Institute trials, these investigators were able to prove “credibility” in the intention-to-treat analysis, as only four patients did not receive treatment and all randomly assigned patients were evaluated, Dr. Melero said. Also lending credibility to the results were the stratification factors (prior treatment with BRAF mutation status, treatment line, and center) and the fact that the results with tumor-infiltrating lymphocytes [TIL] therapy mirror those of an important earlier trial.¹ “That provides another level of confidence that we are talking about a real result,” he commented.

However, Dr, Melero acknowledged, the process of TIL therapy is difficult and labor-intensive. It may be possible to improve the process, he suggested, by selecting the “fittest” TILs, by applying gene transfer and gene engineering, by using “younger” TIL cultures, by combining TILs with other immunotherapies or vaccines, and by injecting part of the dose intratumorally or via other means of “enhancing traffic” to the tumors.

There is also a need for predictive biomarkers that will guide the selection of patients, the tumor ,or the infusion product, and there are logistical hurdles to implementation that must be overcome, he added. Other issues to resolve include the funding of research and pricing.

Selecting Patients for TIL Therapy

That said, TIL therapy could become a means of stabilizing patients after they fail to respond to anti–PD-1 agents and could eventually apply to as many as 7,000 to 15,000 patients with melanoma. In that case, Dr. Melero envisions the incorporation of TIL therapy as follows:

For Surgical Candidates: Proceed with surgery, consider adjuvant treatment with a checkpoint inhibitor, and consider culture of TILs (for later therapy).

For Surgical Candidates With a Good Performance Status: Treatment recommendations include a clinical trial, ipilimumab plus nivolumab, single-agent nivolumab or pembrolizumab, talimogene laherparepvec (T-VEC), and ultimately TIL therapy for appropriate patients.  

For Surgical Candidates With a Poor Performance Status: The previous recommendations (and others), with TIL therapy to be considered if the performance status improves.

Along with further development in melanoma, various companies are in early-phase research with TIL therapy in non–small cell lung, head and neck, cervical, and renal cell cancers. 

DISCLOSURE: Dr. Melero has served as a consultant to Bristol Myers Squibb, AstraZeneca, Roche, Genmab, Pharmamar, Alligator, Highlight Therapeutics, F-STAR, Numab, Pieris, Third Rock, Boston Therapeutics, Gossamer, Amunix, and Immunocore.

REFERENCE

1. Goff SL, Dudley ME, Citrin DE, et al: Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 34:2389-2397, 2016.