The TCR in CAR T cell therapy: use it or lose it?

Chimeric antigen receptor (CAR) T cell therapy has become an indispensable immunotherapy for the treatment of some hematologic cancers, but still faces numerous challenges in the form of antigen escape, variable patient responses, toxicities, limited CAR T cell persistence, and high cost, particularly against solid tumors. This Review discusses the potential role of the endogenous T cell receptor (TCR) as either a hindrance or partner to CAR T cell function. Specifically, we discuss the differences and similarities between CAR and TCR structure and function, findings supporting the value of TCR elimination in CAR T cells, and, in contrast, data in support of retaining and utilizing the endogenous TCR in CAR T cell therapy. We make the case that, while TCR-knockout systems may improve aspects such as the universality, cost, and CAR expression of CAR therapies, the endogenous TCR continues to play a significant role in maintaining CAR T cell persistence and can be used to augment CAR T cell therapeutic phenotypes. Overall, we highlight the uncertainties that persist within the field of CAR T cell therapy and outline emerging evidence and directions regarding the CAR T cell TCR that have the potential to transform patient outcomes.