Optimizing TIL therapy for uveal melanoma: lessons learned and unlearned from cutaneous melanoma

Adoptive transfer of tumor infiltrating lymphocytes (TIL-ACT) is a personalized cancer therapy that harnesses the anti-tumor activity of tumor resident T cells through ex vivo activation and expansion. This therapy involves the infusion of a single dose of ex vivo expanded TIL together with high dose IL-2 following a preparative lymphodepleting chemotherapy. The United States Food and Drug Administration approved lifileucel in 2024 as the first autologous TIL product for patients with advanced cutaneous melanoma (CM), adding to the list of approved immunotherapies for this highly immunogenic cancer. However, the role for TIL-ACT in other solid tumors is unclear, especially for poorly immunogenic cancers with low tumor mutational burden. In this review, we describe the historical development of TIL-ACT, summarize the clinical results in advanced CM, and describe the novel application of TIL-ACT to metastatic uveal melanoma (UM), a prototypic immunotherapy-resistant solid tumor. We will highlight key biologic differences between CM and UM, their consequential influence on the manufacturing of UM-specific TIL products, and the development of novel biomarkers for precision TIL-ACT for metastatic UM.