TOP CAR with TMIGD2 as a safe and effective costimulatory domain in CAR cells treating human solid tumors

• Published in: Science advances Vol. 10; no. 19; p. eadk1857
• Main Authors: Nishimura, Christopher D, Corrigan, Devin, Zheng, Xiang Yu, Galbo, Jr, Phillip M, Wang, Shan, Liu, Yao, Wei, Yao, Suo, Linna, Cui, Wei, Mercado, Nadia, Zheng, Deyou, Zhang, Cheng Cheng, Zang, Xingxing
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 10.05.2024
• Subjects: Animals; B7 Antigens - immunology; B7 Antigens - metabolism; Biomedicine and Life Sciences; Cancer; CD28 Antigens - immunology; CD28 Antigens - metabolism; Cell Line, Tumor; Humans; Immunology; Immunotherapy, Adoptive - methods; Mice; Neoplasms - immunology; Neoplasms - therapy; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; SciAdv r-articles; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Xenograft Model Antitumor Assays
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adk1857

Chimeric antigen receptor (CAR)-T cell therapy shows impressive efficacy treating hematologic malignancies but requires further optimization in solid tumors. Here, we developed a TMIGD2 optimized potent/persistent (TOP) CAR that incorporated the costimulatory domain of TMIGD2, a T and NK cell costimulator, and monoclonal antibodies targeting the IgV domain of B7-H3, an immune checkpoint expressed on solid tumors and tumor vasculature. Comparing second- and third-generation B7-H3 CARs containing TMIGD2, CD28, and/or 4-1BB costimulatory domains revealed superior antitumor responses in B7-H3.TMIGD2 and B7-H3.CD28.4-1BB CAR-T cells in vitro. Comparing these two constructs using in vivo orthotopic human cancer models demonstrated that B7-H3.TMIGD2 CAR-T cells had equivalent or superior antitumor activity, survival, expansion, and persistence. Mechanistically, B7-H3.TMIGD2 CAR-T cells maintained mitochondrial metabolism; produced less cytokines; and established fewer exhausted cells, more central memory cells, and a larger CD8/CD4 T cell ratio. These studies demonstrate that the TOP CAR with TMIGD2 costimulation offered distinct benefits from CD28.41BB costimulation and is effective against solid tumors.