BACKGROUND: The receptor tyrosine kinases TAM family (TYRO3, AXL, and MERTK) are highly expressed in multiple forms of cancer cells and tumor-associated macrophages and promote the development of cancers including pancreatic tumor. Targeting TAM receptors could be a promising therapeutic option. METHODS: We designed a novel CAR based on the extracellular domain of growth arrest-specific protein 6 (GAS6), a natural ligand for all TAM members. The ability of CAR-T to kill pancreatic cancer cells is tested in vitro and in vivo, and the safety is evaluated in mice and nonhuman primate. RESULTS: GAS6-CAR-T cells efficiently kill TAM-positive pancreatic cancer cell lines, gemcitabine-resistant cancer cells, and cancer stem-like cells in vitro. GAS6-CAR-T cells also significantly suppressed the growth of PANC1 xenografts and patient-derived xenografts in mice. Furthermore, these CAR-T cells did not induce obvious side effects in nonhuman primate or mice although the CAR was demonstrated to recognize mouse TAM. CONCLUSIONS: Our findings indicate that GAS6-CAR-T-cell therapy may be effective for pancreatic cancers with low toxicity.
Author Info:
(1) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research C
enter for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. (2) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. (3) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. (4) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. (5) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. (6) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. (7) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. (8) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. (9) Core Facilities of West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. zjie@scu.edu.cn. (10) Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. zhaoxudong@wchscu.cn.
