Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer

• Published in: Journal of hematology and oncology Vol. 12; no. 1; p. 18
• Main Authors: Lv, Jiang, Zhao, Ruocong, Wu, Di, Zheng, Diwei, Wu, Zhiping, Shi, Jingxuan, Wei, Xinru, Wu, Qiting, Long, Youguo, Lin, Simiao, Wang, Suna, Wang, Zhi, Li, Yang, Chen, Yantao, He, Qing, Chen, Suimin, Yao, Huihui, Liu, Zixia, Tang, Zhaoyang, Yao, Yao, Pei, Duanqing, Liu, Pentao, Zhang, Xuchao, Zhang, Zhenfeng, Cui, Shuzhong, Chen, Ren, Li, Peng
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.02.2019; BioMed Central; BMC
• Subjects: Animal models; Animals; Antigens; Antigens, Neoplasm - pharmacology; Antigens, Neoplasm - therapeutic use; Antitumor activity; Breast cancer; Cancer; Cancer metastasis; Cancer research; Cancer treatment; Care and treatment; CD28 antigen; Cell activation; Cell surface; Chimeric antigen receptor T cells; Chimeric antigen receptors; Cytokines; Cytotoxicity; DAP10 protein; Disease Models, Animal; Gastric cancer; Genetic aspects; GPI-Linked Proteins - pharmacology; GPI-Linked Proteins - therapeutic use; Health aspects; Hematology; Humans; Immunodeficient mice; Immunotherapy; Intracellular signalling; Lung cancer; Lymphocytes; Lymphocytes T; Mesothelin; Mesothelioma; Metastases; Metastasis; Mice; Oncology; Pancreas; Pancreatic cancer; Phenotypes; Phenotyping; Physiological aspects; Receptors, Chimeric Antigen - immunology; Regression analysis; Stomach cancer; Stomach Neoplasms - genetics; T cells; T-Lymphocytes - immunology; Transfection; Tumors; Xenografts; China; Asia; Mesothelin; Chimeric antigen receptor T cells; Immunodeficient mice; Gastric cancer; Immunotherapy
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-019-0704-y

Gastric cancer (GC) is a common cancer in Asia and currently lacks a targeted therapy approach. Mesothelin (MSLN) has been reported to be expressed in GC tissue and could be targeted by chimeric antigen receptor (CAR) T cells. Mesothelin targeting CAR-T has been reported in mesothelioma, lung cancer, breast cancer, and pancreas cancer. However, the feasibility of using anti-MSLN CAR T cells to treat GC remains to be studied. We verified MSLN expression in primary human GC tissues and GC cell lines and then redirected T cells with a CAR containing the MSLN scFv (single-chain variable fragment), CD3ζ, CD28, and DAP10 intracellular signaling domain (M28z10) to target MSLN. We evaluated the function of these CAR T cells in vitro in terms of cytotoxicity, cytokine secretion, and surface phenotype changes when they encountered MSLN+ GC cells. We also established four different xenograft GC mouse models to assess in vivo antitumor activity. M28z10 T cells exhibited strong cytotoxicity and cytokine-secreting ability against GC cells in vitro. In addition, cell surface phenotyping suggested significant activation of M28z10 T cells upon target cell stimulation. M28z10 T cells induced GC regression in different xenograft mouse models and prolonged the survival of these mice compared with GFP-transduced T cells in the intraperitoneal and pulmonary metastatic GC models. Importantly, peritumoral delivery strategy can lead to improved CAR-T cells infiltration into tumor tissue and significantly suppress the growth of GC in a subcutaneous GC model. These results demonstrate that M28z10 T cells possess strong antitumor activity and represent a promising therapeutic approach to GC.