Zhang, Li, and Cao et al. identified OX40 as a potential CAR function enhancer in a screen of 12 antigen-independent co-stimulatory receptors. OX40 expression in anti-CD20, 41BB, Zeta CAR T cells (20BBZ-OX40 CAR-T) enhanced proliferation and cytotoxicity, reduced apoptosis, and downregulated exhaustion markers upon repetitive OX40L stimulation. In xenograft tumor models, 20BBZ-OX40 CAR-T persisted and proliferated in vivo and demonstrated enhanced antitumor activity. In 5 patients with metastatic B cell lymphoma, a single dose of 20BBZ-OX40 CAR-T showed significant proliferation and objective responses (2 CR and 3 PR) without severe side effects.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. Joint International Resear
Author Info: (1) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. Joint International Research Laboratory of Metabolic and Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China. (2) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. Joint International Research Laboratory of Metabolic and Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China. (3) Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China. (4) Shanghai Longyao Biotechnology Limited, Shanghai 201203, China. (5) Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China. (6) Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China. (7) Cancer Institute, Xuzhou Medical University, Xuzhou 221002, China. (8) Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China. (9) Cancer Institute, Xuzhou Medical University, Xuzhou 221002, China. (10) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (11) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. xuanmingyang@sjtu.edu.cn. Joint International Research Laboratory of Metabolic and Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
