Abstract
The recent U.S. FDA approval of lifileucel, a non-engineered, autologous tumor-infiltrating lymphocyte (TIL) therapy, for unresectable or metastatic melanoma represents a major milestone for cellular therapies in solid tumors. This review examines the clinical foundation, regulatory development, limitations, and evolution of TIL therapy in metastatic melanoma. Randomized academic data from the phase III M14TIL trial established the efficacy of TIL therapy. The C-144-01 study leading to lifileucel approval demonstrated median duration of response of 36.5 months, median overall survival (OS) of 13.9 months, and estimated 5-year OS rate of 19.7%, a major advance in this anti-PD-1/PD-L1 resistant cohort without effective treatment options. Despite durable responses, classical TIL therapy requires intensive nonmyeloablative lymphodepletion and high-dose interleukin-2 (IL-2), contributing to substantial toxicity and treatment-related mortality that remain barriers to broader implementation. We discuss safety-driven trial terminations related to cytokine augmentation and feasibility or strategic factors underlying discontinuation of programs, underscoring translational challenges beyond biologic efficacy. Engineered TIL platforms aim to improve persistence and reduce systemic cytokine dependence. OBX-115, designed with regulatable membrane-bound IL-15 expression, eliminates the need for IL-2 infusion and has shown early clinical activity. KSQ-001EX uses CRISPR/Cas9 to inactivate SOCS1, while KSQ-004EX additionally targets Regnase-1 to enhance TIL function. Emerging strategies including IL-2-independent expansion platforms, PD-1-edited TILs, and neoantigen-enriched products illustrate ongoing innovation. TIL therapy remains among the most promising strategies in melanoma and solid tumors after immunotherapy failure. Ongoing research aims to optimize cell dose, phenotype, tumor procurement, treatment sequencing, and rational combinations to improve durable benefit.