Incorporation of a hinge domain improves the expansion of chimeric antigen receptor T cells
| Autor: | Baiheng Li, Xin Du, Peng Li, Duanqing Pei, Peilong Lai, Yangqiu Li, Yunxin Lai, Lin Simiao, Xinru Wei, Suna Wang, Jianyu Weng, Qiubin Liang, Le Qin, Yao Yao, Pentao Liu, Qiting Wu, Yi-Long Wu, Ruocong Zhao, Xu-Chao Zhang |
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| Rok vydání: | 2017 |
| Předmět: |
Cytotoxicity
Immunologic Expansion 0301 basic medicine Cancer Research Receptor ErbB-2 T-Lymphocytes medicine.medical_treatment Protein Engineering Immunotherapy Adoptive Mice 0302 clinical medicine MUC1 CD19 biology CAR T cell lcsh:Diseases of the blood and blood-forming organs Hematology lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Neoplasm Proteins Cell biology Cytokine Oncology Mesothelin 030220 oncology & carcinogenesis Cytokines Heterografts Hinge domain Rapid Communication Antigens CD19 Protein domain Receptors Antigen T-Cell GPI-Linked Proteins lcsh:RC254-282 CD4+ T cell 03 medical and health sciences Protein Domains Antigens Neoplasm In vivo Cell Line Tumor medicine Animals Humans Molecular Biology Cell Proliferation lcsh:RC633-647.5 Cell growth Mucin-1 Virology Chimeric antigen receptor In vitro 030104 developmental biology biology.protein human activities |
| Zdroj: | Journal of Hematology & Oncology, Vol 10, Iss 1, Pp 1-11 (2017) Journal of Hematology & Oncology |
| ISSN: | 1756-8722 |
| Popis: | Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0437-8) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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