Tumor-infiltrating lymphocyte expansion protocols for adoptive cell therapy in cancer

Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs) has emerged as an innovative strategy in cancer immunotherapy, especially in the treatment of solid tumors. This review provides a comprehensive analysis of current TILs expansion protocols, with a focus on strategies aimed at optimizing their performance, feasibility and functionality. The classical TILs expansion protocol is based on a two-step process: a rapid pre-expansion phase (Pre-REP), followed by a rapid expansion phase (REP), in which high concentrations of interleukin-2 (IL-2) are used. In recent years, various modifications have been incorporated into the protocol with the aim of improving its efficiency, including the use of alternative combinations of cytokines such as IL-7, IL-15, and IL-21, as well as the replacement of irradiated feeder cells or anti-CD3 antibodies with other strategies. Furthermore, advances such as the targeting of TILs specific to neoantigens, the development of CAR-TILs, the application of artificial intelligence, and the genetic modification of TILs have contributed to expanding both the applicability and efficacy of this therapy. The clinical success of Lifileucel with the recent FDA approval of underscore the translational potential of TILs-based therapies. However, significant challenges remain, including time and production costs. This review examines ongoing clinical trials and combination therapeutic strategies, such as the use of immune checkpoint inhibitors. As research progresses, optimization of TILs expansion protocols will be critical to improving clinical outcomes and broadening the applicability of this personalized immunotherapy in oncology.