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

作者：Jiang Lv, Ruocong Zhao, Di Wu, Diwei Zheng, Zhiping Wu, Jingxuan Shi, Xinru Wei, Qiting Wu, Youguo Long, Simiao Lin, Suna Wang, Zhi Wang, Yang Li, Yantao Chen, Qing He, Suimin Chen, Huihui Yao, Zixia Liu, Zhaoyang Tang, Yao Yao, Duanqing Pei, Pentao Liu, Xuchao Zhang, Zhenfeng Zhang, Shuzhong Cui, Chen Ren, Peng Li · 发表于：Journal of Hematology & Oncology · 年份：2019 · DOI：10.1186/s13045-019-0704-y · 被引用次数：141 · 研究领域：CAR-T cell therapy research、Occupational and environmental lung diseases、Cancer Immunotherapy and Biomarkers

BACKGROUND: 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. METHODS: 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. RESULTS: 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 i...