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Development of mesothelin-specific CAR NK-92 cells for the treatment of gastric cancer

Bihui CaoDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaManting LiuDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaJingjun HuangDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaJingwen ZhouDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaJunping LiDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaHui LianDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaWensou HuangDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaYongjian GuoDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaShuo YangDepartment of Pharmacy, Guangzhou Medical University, 511436, ChinaLiteng LinDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaMingyue CaiDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaCheng ZhiDepartment of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, ChinaJingqiang WuDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaLicong LiangDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaYuling HuDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaHong‐Ming HuDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaJinping HeDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaBaoxia LiangDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, ChinaQi ZhaoMoE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, 999078 ChinaKangshun ZhuDepartment of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, China

2021en

ABI

Annotatsiya

The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR NK cell efficacy. It has been reported that mesothelin (MSLN) may be an ideal immunotherapy target for gastric cancer. However, the feasibility of using anti-MSLN CAR NK cells to treat gastric cancer remains to be studied. Methods: MSLN expression in primary human gastric cancer, normal tissues and cell lines were detected. MSLN and CD19 targeted CAR NK-92 (MSLN-and CD19-CAR NK) cells were constructed, purified and verified. N87, MKN-28, AGS and Huh-7 cells expressing the GFP and luciferase genes were transduced. Celland patient-derived xenograft (PDX) were established via NSG mice. The ability of MSLN-CAR NK cells to kill MSLN-positive gastric cancer cells were evaluated in vitro and in vivo. Results: MSLN-CAR NK cells can specifically kill MSLN-positive gastric cancer cells (N87, MKN-28 and AGS), rather than MSLN negative cell (Huh-7), in vitro. Moreover, compared with parental NK-92 cells and CD19-CAR NK cells, stronger cytokine secretions were secreted in MSLN-CAR NK cells cocultured with N87, MKN-28 and AGS. Furthermore, MSLN-CAR NK cells can effectively eliminate gastric cancer cells in both subcutaneous and intraperitoneal tumor models. They could also significantly prolong the survival of intraperitoneally tumor-bearing mice. More importantly, the potent antitumor effect and considerable NK cell infiltration were observed in the patient-derived xenograft treated with MSLN-CAR NK cells, which further warranted the therapeutic effects of MSLN-CAR NK cells to treat gastric cancer.

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Identifikatorlar

DOI: 10.7150/ijbs.64630

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