The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity.

Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors， but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC)， a chimeric receptor that co-opts the endogenous TCR， induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro， and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model， TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy， reduced toxicity， and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67 CD8 T cells， demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells.