The US Food and Drug Administration (FDA) recently approved a tumor-infiltrating lymphocyte (TIL) therapy referred to as “Amtagvi”. This approval was fast-tracked for the use in patients with unresectable or metastatic melanoma. Dr. Steven Rosenberg who currently works for the US National Cancer Institute (NCI) pioneered the idea of TIL therapy and, in 1988, first showed the significant effect of adoptive cell therapies in solid tumors.
TIL therapy is a form of adoptive cell therapy in which tumor samples are taken from the patient and specific immune cells, known as T cells, are purified and expanded. Specific drugs then isolate tumor-specific T cells that have neoantigens or surface proteins specific to the tumor. The T cells with neoantigens have a higher affinity to identify and lyse or kill cancer cells. Once these cells are expanded, they are then reinfused into patients ready to deplete the tumor.
The FDA approval is based on an open-label phase II clinical trial in 73 advanced melanoma patients. Unfortunately, these patients were resistant to another therapy known as immune checkpoint inhibitors (ICI). ICIs block the interaction between T cells and adjacent cells to promote activation and target the tumor. TIL therapy treatment in ICI resistant melanoma patients resulted in 43.5% of patients being symptom-free for 12-months or longer. Additionally, 4.1% of the patients had a complete response (CR). Side effects associated with the treatment included low blood count, severe infection accompanied with cardiovascular and kidney risk. The adverse effects were noted due to the necessary procedures prior and post TIL therapy. Prior to TIL infusion, patients are depleted of lymphocytes to make room for the infusion of the TILs. Post-infusion, interleukin-2 (IL-2) was given to help further expand TIL growth in the body. Interestingly, IL-2 is a protein known as a cytokine which helps direct cell function. Overall, the phase II clinical trial was concluded as a success and necessary for patients with limited therapeutic options.
Currently, a phase III clinical trial is underway to confirm optimal outcomes. The results from this trial will be available between 2028-2030. TIL therapy is a popular cell adoptive transfer therapy similar to chimeric antigen receptor (CAR) T-cell therapy, which engineer patient T-cells to target tumor neoantigens. Billions of dollars of funding have gone into pushing CAR T-cell development and trying to get it approved for various tumor types. Unfortunately, CAR T-cell therapy still has not shown efficacy in solid tumors compared to TIL therapy.
Although TIL therapy has shown efficacy in solid tumors, concerns have been raised about how they are developed. TIL isolation and expansion from the tumor instead of blood has raised manufacturing obstacles making the therapy difficult to execute. Tumors in individual patients can vary tremendously, particularly the tumor neoantigens. Additionally, IL-2 treatment post-TIL infusion increase toxicity that patients with cancer may not be able to tolerate.
Overall, both academic and industrial labs are working to improve TIL therapy. With the recent FDA approval, TIL therapy will provide novel treatment to a wider range of patients that would not otherwise have access. FDA approval for TIL therapy is a milestone for the expansion and advancement of immunotherapy.