On February 16, the Food and Drug Administration (FDA) approved Amtagvi (lifileucel), the first tumor-infiltrating lymphocyte (TIL) therapy, for people with advanced melanoma who have tried other treatments. The accelerated approval is the result of nearly 40 years of research to develop T-cell therapies for solid tumors, but further follow-up is needed to see whether the treatment improves survival.

“Unresectable or metastatic melanoma is an aggressive form of cancer that can be fatal,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a news release. “The approval of Amtagvi represents the culmination of scientific and clinical research efforts leading to a novel T-cell immunotherapy for patients with limited treatment options.”

Treatment with Amtagvi, from Iovance Biotherapeutics, involves collecting T cells from an individual’s tumor, multiplying them in a laboratory to create billions of cells and infusing them back into the same patient. T cells, the immune system’s cancer-fighting soldiers, are often unable to get inside tumors to do their job. But tumor-infiltrating lymphocytes (TILs), which are obtained from a tumor biopsy sample, are able to recognize distinctive tumor markers and attack that person’s specific cancer. These cells naturally fight cancer without reprogramming, but eventually, they become exhausted, and there are usually not enough of them to keep malignancy under control.

Like stem cell transplants and CAR-T therapy, which reprograms T cells by adding an artificial receptor, treatment with Amtagvi is not an easy process. The patient first receives strong chemotherapy to kill off their existing immune cells and make room for the tumor-specific ones. After the TIL infusion, they also receive interleukin-2 (IL-2, or Proleukin), a cytokine that stimulates T-cell growth and activity.

Amtagvi is the first T-cell therapy to be approved for a solid tumor. While stem cell transplants and CAR-T therapy are effective against blood cancers, such as leukemia and lymphoma, they do not work well for solid tumors. Melanoma, a so-called “hot” tumor that has many mutations to attract immune cells, is the easiest type of solid tumor to treat with immunotherapy. Nearly 8,300 people are expected to die of melanoma this year.

Researchers have been working on T-cell therapies for decades, facing many roadblocks along the way. Steven Rosenberg, MD, of the National Cancer Institute (NCI), discovered TILs in the 1980s and pioneered the development of adoptive cell transfer, but this approach has mainly been limited to academic cancer centers. In 2018, Cancer Health interviewed Jamie Goldfarb, who participated in an early TIL clinical trial at the NCI in 2011 and achieved complete remission.

The approval of Amtagvi is based on results from the C-144-01 trial (NCT02360579), a multicenter Phase II study that enrolled patients with inoperable or metastatic melanoma. Just over half were men, most were white and the median age was 56 years. They had previously been treated with PD-1/PD-L1 immune checkpoint inhibitors and targeted therapy, if appropriate.

Initially, 111 patients underwent tumor removal. Of these, 22 did not receive Amtagvi for various reasons, including inability to manufacture the product, disease progression or death. The remaining 89 participants in this single-arm open-label trial received Amtagvi; there was no control group. Seven people were excluded from the analysis due to problems with the product.

Among the 73 people who received an optimal dose of Amtagvi, the objective response rate—meaning tumor regression—was 32%, including three people (4%) with complete responses. The median time to initial response was 1.5 months. Among the responders, 44% were still alive without disease progression at 12 months. The median duration of response was not reached because a majority were still responding. In a larger pooled analysis of 153 patients, the objective response rate was 31%, the complete response rate was 5% and 42% of responders maintained a durable response at 18 months. Median progression-free and overall survival at the time of the analysis were 4.1 months and 13.9 months, respectively.

Amtagvi is generally safe, but side effects are common. Many of the adverse effects of the treatment, including hair loss, low blood cell counts and increased susceptibility to infections, are attributable to the conditioning chemotherapy. IL-2 can also cause severe side effects. The prescribing information for Amtagvi includes a boxed warning about the risk of prolonged severe blood cell deficiencies, internal organ hemorrhage, severe infections and heart, lung and kidney impairment.

“The approval of Amtagvi offers hope to those with advanced melanoma who have progressed following initial standard of care therapies, as the current treatment options are not effective for many patients,” said Samantha Guild, JD, president of AIM at Melanoma Foundation. “This one-time cell therapy represents a promising innovation for the melanoma community, and we are excited by its potential to transform care for patients who are in dire need of additional therapeutic options.”

But cost and access could be an issue. Amtagvi must be custom-made for each patient, a process that takes about three weeks. It will be manufactured at Iovance’s facility in Philadelphia. Patients must be hospitalized before, during and after treatment. Some 30 authorized treatment centers are ready to begin administering Amtagvi, and more will come online soon. The company set the price for the treatment, which is administered only once, at $515,000, comparable to CAR-T therapy. A patient support program, IovanceCares, will offer co-pay support, financial assistance and travel and lodging assistance for eligible patients.

Drugs that receive accelerated approval based on overall response rates are expected to undergo further testing to confirm that they do, in fact, offer clinical benefits, such as improved survival, and the FDA can rescind the approval if they fail to measure up. A Phase III confirmatory trial dubbed TILVANCE-301 (NCT05727904) is now underway.

Researchers are also testing dozens of TILs for other types of solid tumors—including some “colder” tumors that traditionally do not respond well to immunotherapy—and several companies have candidates in the pipeline. Iovance is testing a similar TIL therapy (LN-145) for lung cancer, but that study was placed on hold in December after a patient death. In 2022, Rosenberg and colleagues reported that TIL therapy plus an immune checkpoint inhibitor shows promise for metastatic breast cancer in an ongoing Phase II trial (NCT01174121).

“This landmark FDA approval reflects significant advancements in TIL cell therapy since we initially showed that TIL cells isolated from patients with metastatic melanoma could be expanded in the lab and returned to the patient to mediate cancer regression,” Rosenberg said in an Iovance news release. “This approval is transformative for the entire research field and supports continued investigation of TIL cell therapy across additional types of solid tumors.”

Click here for full prescribing information for Amtagvi.

Click here for more news about immunotherapy.