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

Sci Transl Med. 2021 Mar 24;13(586):eabb5191. doi: 10.1126/scitranslmed.abb5191.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Immunotherapy, Adoptive
  • Neoplasms* / therapy
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen*
  • T-Lymphocytes


  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen