Helsen et al. constructed an MHC-independent T cell antigen coupler (TAC), a chimeric receptor that consists of an antigen-binding domain, a TCR recruitment domain, and a CD4+ or CD8+ co-receptor, and signals through the endogenous TCR. TAC-engineered T cells were effective against solid and liquid tumor targets in murine xenograft models with no observed autoactivation. TAC-engineered T cells accumulated faster and more exclusively within tumor tissues than first and second generation CAR T cells, were proliferative only within the tumor, and induced more efficient antitumor responses with less 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.