Liu, Liu, and Wang et al. engineered an antibody Vh-TCR Cα, Vl-TCR Cβ chimeric receptor called STAR in which the parental antibody confers antigen specificity and the TCR engages intact endogenous CD3 signaling machinery. STAR-T cells showed potent effector function, better proliferation, and less exhaustion in vitro; robust antitumor activity and higher sensitivity to antigen-low solid tumors in vivo; and T cell signaling and gene expression similar to TCR-T cells, but distinct from CAR-T cells. STAR-T cells maintained a resting phenotype, avoided early dysfunction, and were compatible with additional modules for versatile function.
Contributed by Shishir Pant
ABSTRACT: Chimeric antigen receptor T (CAR-T) cell therapies have demonstrated high response rate and durable disease control for the treatment of B cell malignancies. However, in the case of solid tumors, CAR-T cells have shown limited efficacy, which is partially attributed to intrinsic defects in CAR signaling. Here, we construct a double-chain chimeric receptor, termed as synthetic T cell receptor (TCR) and antigen receptor (STAR), which incorporates antigen-recognition domain of antibody and constant regions of TCR that engage endogenous CD3 signaling machinery. Under antigen-free conditions, STAR does not trigger tonic signaling, which has been reported to cause exhaustion of traditional CAR-T cells. Upon antigen stimulation, STAR mediates strong and sensitive TCR-like signaling, and STAR-T cells exhibit less susceptibility to dysfunction and better proliferation than traditional 28zCAR-T cells. In addition, STAR-T cells show higher antigen sensitivity than CAR-T cells, which holds potential to reduce the risk of antigen loss-induced tumor relapse in clinical use. In multiple solid tumor models, STAR-T cells prominently outperformed BBzCAR-T cells and generated better or equipotent antitumor effects to 28zCAR-T cells without causing notable toxicity. With these favorable features endowed by native TCR-like signaling, STAR-T cells may provide clinical benefit in treating refractory solid tumors.