T Cell Receptors for Gene Transfer in Adoptive T Cell Therapy

The past decade has seen enormous progress in cancer immunotherapy. Checkpoint inhibitors are a class of immunotherapy that act to recruit endogenous T cells of a patient's immune system against cancer-associated peptide-MHC antigens. In this process, mutated antigenic peptides referred to as neoantigens often serve as the target on cancer cells that are recognized by the T cell receptor (TCR) on endogenous T cells. Another successful immunotherapy has involved adoptive T cell therapy, where therapeutic doses of T cells expressing a gene for an anti-cancer receptor are delivered to a patient. This approach has been used primarily against hematopoietic cancers using synthetic receptors called chimeric antigen receptors (CARs). CARs typically contain an antibody fragment (single-chain Fv, scFv) against a cancer cell surface antigen such as the B cell molecule CD19. While therapeutic CARs (and full antibodies) target antigens expressed on cell surfaces, TCRs can target a much larger array of intracellular proteins by binding to any cellular peptide associated with an MHC product. These cancer targets include self-peptides from aberrantly expressed/overexpressed proteins or neoantigens. In this review, we discuss the use of TCRs in adoptive T cell therapy and their target antigens. We focus on two properties that impact sensitivity, potency, and possible toxic cross-reactivity of TCR-mediated therapy: (1) the affinity of the TCR for the target antigen, and (2) the density of the target antigen. Finally, we provide a comprehensive listing of the current clinical trials that involve TCRs in adoptive T cell cancer therapy.