Research ArticleCancer

Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors

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Science Translational Medicine  24 Mar 2021:
Vol. 13, Issue 586, eabb5191
DOI: 10.1126/scitranslmed.abb5191

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The STAR of the show

Chimeric antigen receptor (CAR) T cells have revolutionized treatment for hematological cancers, but this success has not translated to solid tumors. To address the challenge of treating solid tumors, Liu et al. went back to basics. Rather than further modifying CAR-T cells, the authors instead engineered a synthetic T cell receptor and antigen receptor (STAR) that combines the specificity of a CAR and the internal signaling machinery of an endogenous T cell receptor. STAR-T cells outperformed their CAR-T cell counterparts in controlling multiple murine tumors and did not display evidence of exhaustion frequently observed in CAR-T cells. These results suggest that STAR-T cells may be an attractive option for treating patients with solid tumors.

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.

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