Incorporation of a hinge domain improves the expansion of chimeric antigen receptor T cells

• Published in: Journal of hematology and oncology 2017-03, Vol.10 (1), p.68-68, Article 68
• Main Authors: Qin, Le, Lai, Yunxin, Zhao, Ruocong, Wei, Xinru, Weng, Jianyu, Lai, Peilong, Li, Baiheng, Lin, Simiao, Wang, Suna, Wu, Qiting, Liang, Qiubin, Li, Yangqiu, Zhang, Xuchao, Wu, Yilong, Liu, Pentao, Yao, Yao, Pei, Duanqing, Du, Xin, Li, Peng
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antigens, CD19 - immunology; Antigens, Neoplasm - immunology; Antitumor activity; Cancer; CAR T cell; CD19; CD19 antigen; CD4 antigen; CD4+ T cell; Cell culture; Cell Line, Tumor; Cell migration; Cell Proliferation; Chimeric antigen receptors; Cytokines - biosynthesis; Cytotoxicity; Cytotoxicity, Immunologic; ErbB-2 protein; Expansion; GPI-Linked Proteins - immunology; Hematology; Heterografts; Hinge domain; Humans; Immunotherapy; Immunotherapy, Adoptive - methods; Intracellular signalling; Leukemia; Lymphocytes; Lymphocytes T; Mesothelin; Mice; Mucin-1 - immunology; Neoplasm Proteins - immunology; Oncology; Penicillin; Protein Domains - genetics; Protein Domains - immunology; Protein Engineering; Rapid Communication; Receptor, ErbB-2 - immunology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Rodents; T cell receptors; T-Lymphocytes - cytology; T-Lymphocytes - immunology
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-017-0437-8

Multiple iterations of chimeric antigen receptors (CARs) have been developed, mainly focusing on intracellular signaling modules. However, the effect of non-signaling extracellular modules on the expansion and therapeutic efficacy of CARs remains largely undefined. We generated two versions of CAR vectors, with or without a hinge domain, targeting CD19, mesothelin, PSCA, MUC1, and HER2, respectively. Then, we systematically compared the effect of the hinge domains on the growth kinetics, cytokine production, and cytotoxicity of CAR T cells in vitro and in vivo. During in vitro culture period, the percentages and absolute numbers of T cells expressing the CARs containing a hinge domain continuously increased, mainly through the promotion of CD4+ CAR T cell expansion, regardless of the single-chain variable fragment (scFv). In vitro migration assay showed that the hinges enhanced CAR T cells migratory capacity. The T cells expressing anti-CD19 CARs with or without a hinge had similar antitumor capacities in vivo, whereas the T cells expressing anti-mesothelin CARs containing a hinge domain showed enhanced antitumor activities. Hence, our results demonstrate that a hinge contributes to CAR T cell expansion and is capable of increasing the antitumor efficacy of some specific CAR T cells. Our results suggest potential novel strategies in CAR vector design.