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.
Author Info: (1) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Center for Life Sciences, Beijing 100084, China. (2) Institute for
Author Info: (1) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Center for Life Sciences, Beijing 100084, China. (2) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (3) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Center for Life Sciences, Beijing 100084, China. (4) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (5) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (6) China Immunotech (Beijing) Biotechnology Co., Ltd, Beijing 102206, China. (7) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (8) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Center for Life Sciences, Beijing 100084, China. (9) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (10) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (11) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China. (12) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. linxin307@tsinghua.edu.cn zhaoxueqiang@mail.tsinghua.edu.cn. (13) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. linxin307@tsinghua.edu.cn zhaoxueqiang@mail.tsinghua.edu.cn. Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
