Results of the world’s first comparative phase III trial probing the efficacy of tumor infiltrating lymphocyte (TIL) therapy in solid tumors, support the use of the therapy in patients with advanced metastatic melanoma, an aggressive form of skin cancer. The results were published in The New England Journal of Medicine (NEJM) on December 8, 2022 “Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.”

The trial was led by the Netherlands Cancer Institute in collaboration with the National Center for Cancer Immune Therapy in Copenhagen, and sponsored by the KWF Dutch Cancer Society, ZonMw, the Ministry of Health, Welfare and Sport, Stichting Avento, and other Danish organizations. Based on these results, the Dutch National Health Care Institute will assess the potential of TIL therapy as a standard treatment, so that it can be covered by basic health insurance.

“Ten years ago, melanoma was so deadly that I would be seeing an entirely new patient population every year. Now I’ve been seeing some patients for ten years. This is largely due to the discovery of immunotherapy, which has revolutionized treatment for melanomas. But we still find that about half of people diagnosed with metastatic melanoma lose their lives within five years, so we’re still not where we want to be—not by a long shot, said John Haanen, MD, medical oncologist at the Netherlands Cancer Institute, who led the TIL trial. “The TIL trial has shown that cell therapy using the patient’s own immune cells is an extremely powerful immunotherapy for metastatic melanoma, and that this therapy still offers a high chance of improvement, even if other immunotherapies fail.”

Although early cell therapy clinical trials showed promising results, a comparative phase III trial is necessary to establish TIL therapy as a regular treatment. This international trial was started in 2014 and compared TIL therapy to standard immunotherapy with the checkpoint inhibitor ipilimumab.

In 49% patients with metastatic melanoma who received TIL therapy as part of the trial, the metastases shrunk and in 20% patients, the metastases disappeared completely. This also held true for patients who had already received another treatment before being enrolled in this trial. In contrast, among patients who received ipilimumab, metastases shrunk in only 21% patients, and disappeared in 7% patients. Progression-free survival (PFS) was 53% after six months in patients who received TIL therapy and only 21% in the patients who received ipilimumab. The median PFS in patients on the TIL therapy was seven months, and three months in patients on ipilimumab.

“We also looked at whether they could resume their careers and noticed that people [on TIL therapy] were going back to work,” said physician-scientist Maartje Rohaan, MD, PhD, who coordinated the trial. “That’s wonderful to see.” As a bonus, TIL therapy is more cost-effective than ipilimumab.

The one-time TIL therapy caused some side effects in all participants, as did ipilimumab in 96% patients. The side effects of the TIL therapy—high fevers and chills—are usually not caused by the T cells, but by the chemotherapy pre-treatment, which is required to make room for the billions of T cells administered, and by post-treatments with growth factor interleukin-2, which ensures rapid growth of the administered T cells.

Haanen said, “In the future we would like to find a way to avoid the use of high dose interleukin-2 by developing a more precise form of the treatment by using a growth factor that causes fewer side effects.”

In addition to reducing side effects by modifying the use of growth factor interleukin-2, future plans also include improving survival rates particularly during the period immediately following treatment, refining TIL therapy by administering fewer T cells or genetically modifying T cell receptors, and using TIL therapy to treat other forms of cancers.