Adoptive T-Cell Therapy for Solid Tumors.

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19-expressing B-cell acute lymphocytic leukemia. However, clinical gains to the same magnitude have not been reported in solid tumors. Several known obstacles to CAR T-cell therapy for solid tumors include target antigen identification, effective trafficking to the tumor, robust activation, proliferation, and in vivo cytotoxicity. Beyond these T-cell intrinsic properties, a complex and dynamic immunosuppressive tumor microenvironment in solid tumors hinders T-cell efficacy. Notable advancements in CAR design to include multiple costimulatory molecules, ligands, and soluble cytokines have shown promise in preclinical models, and some of these are currently in early-phase clinical trials. In this review, we discuss selected solid tumor malignancies and relevant preclinical data and highlight clinical trial results that are available. Furthermore, we outline some obstacles to CAR T-cell therapy for each tumor and propose strategies to overcome some of these limitations.