GAS6-based CAR-T cells exhibit potent antitumor activity against pancreatic cancer

• Published in: Journal of hematology and oncology 2023-07, Vol.16 (1), p.77-77, Article 77
• Main Authors: Fan, Jiawei, Yu, Ye, Yan, Lanzhen, Yuan, Yuncang, Sun, Bin, Yang, Dong, Liu, Nan, Guo, Jing, Zhang, Jie, Zhao, Xudong
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antitumor activity; Axl protein; Axl Receptor Tyrosine Kinase; Breast cancer; CAR-T-cell therapy; Cell therapy; Cells; Clinical trials; Cloning; Cytotoxicity; Development and progression; Drug resistance; Flow cytometry; GAS6; Gemcitabine; Health aspects; Hematology; Humans; Kinases; Leukemia; Lung cancer; Lymphocytes; Lymphocytes T; Macrophages; Metastasis; Mice; Oncology; Ovarian cancer; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Peptides; Plasmids; Primates - metabolism; Protein-tyrosine kinase receptors; Proteins; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Receptor Protein-Tyrosine Kinases - therapeutic use; Receptors, Chimeric Antigen; T cells; T-Lymphocytes - metabolism; TAM family; Toxicity; Tumor cell lines; Tumors; Tyrosine; Xenografts
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-023-01467-9

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. 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. 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. Our findings indicate that GAS6-CAR-T-cell therapy may be effective for pancreatic cancers with low toxicity.