TY - JOUR
T1 - A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity
AU - Zhang, Huihui
AU - Li, Fanlin
AU - Cao, Jiang
AU - Wang, Xin
AU - Cheng, Hai
AU - Qi, Kunming
AU - Wang, Gang
AU - Xu, Kailin
AU - Zheng, Junnian
AU - Fu, Yang Xin
AU - Yang, Xuanming
N1 - Funding Information:
X.Y. was supported by The National Key Research and Development Program of China (2016YFC1303400), National Natural Science Foundation of China (81971467 and 81671643), and Shanghai Jiao Tong University Scientific and Technological Innovation Funds. J.C. was supported by Jiangsu Province Social Development Key Projects (BE2017639). The research was funded in part by Shanghai Longyao Biotechnology Limited.
Publisher Copyright:
Copyright © 2021 The Authors.
PY - 2021/1/27
Y1 - 2021/1/27
N2 - Although chimeric antigen receptor (CAR)-modified T cells have shown great success in the treatment of B cell malignancies, this approach has limited efficacy in patients with solid tumors. Various modifications in CAR structure have been explored to improve this efficacy, including the incorporation of two costimulatory domains. Because costimulatory signals are transduced together with T cell receptor signals during T cell activation, we engineered a type of CAR-T cells with a costimulatory signal that was activated independently from the tumor antigen to recapitulate physiological stimulation. We screened 12 costimulatory receptors to identify OX40 as the most effective CAR-T function enhancer. Our data indicated that these new CAR-T cells showed superior proliferation capability compared to current second-generation CAR-T cells. OX40 signaling reduced CAR-T cell apoptosis through up-regulation of genes encoding Bcl-2 family members and enhanced proliferation through increased activation of the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase), and PI3K-AKT (phosphoinositide 3-kinase to the kinase AKT) pathways. OX40 signaling not only enhanced the cytotoxicity of CAR-T cells but also reduced exhaustion markers, thereby maintaining their function in immunosuppressive tumor microenvironments. In mouse tumor models and in patients with metastatic lymphoma, these CAR-T cells exhibited robust amplification and antitumor activity. Our findings provide an alternative option for CAR-T optimization with the potential to overcome the challenge of treating solid tumors.
AB - Although chimeric antigen receptor (CAR)-modified T cells have shown great success in the treatment of B cell malignancies, this approach has limited efficacy in patients with solid tumors. Various modifications in CAR structure have been explored to improve this efficacy, including the incorporation of two costimulatory domains. Because costimulatory signals are transduced together with T cell receptor signals during T cell activation, we engineered a type of CAR-T cells with a costimulatory signal that was activated independently from the tumor antigen to recapitulate physiological stimulation. We screened 12 costimulatory receptors to identify OX40 as the most effective CAR-T function enhancer. Our data indicated that these new CAR-T cells showed superior proliferation capability compared to current second-generation CAR-T cells. OX40 signaling reduced CAR-T cell apoptosis through up-regulation of genes encoding Bcl-2 family members and enhanced proliferation through increased activation of the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase), and PI3K-AKT (phosphoinositide 3-kinase to the kinase AKT) pathways. OX40 signaling not only enhanced the cytotoxicity of CAR-T cells but also reduced exhaustion markers, thereby maintaining their function in immunosuppressive tumor microenvironments. In mouse tumor models and in patients with metastatic lymphoma, these CAR-T cells exhibited robust amplification and antitumor activity. Our findings provide an alternative option for CAR-T optimization with the potential to overcome the challenge of treating solid tumors.
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U2 - 10.1126/scitranslmed.aba7308
DO - 10.1126/scitranslmed.aba7308
M3 - Article
C2 - 33504651
AN - SCOPUS:85100651233
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 578
M1 - eaba7308
ER -