Interleukin-15 and chemokine ligand 19 enhance cytotoxic effects of chimeric antigen receptor T cells using zebrafish xenograft model of gastric cancer

• Published in: Frontiers in immunology Vol. 13; p. 1002361
• Main Authors: Zhou, Zhifeng, Li, Jieyu, Hong, Jingwen, Chen, Shuping, Chen, Mingshui, Wang, Ling, Lin, Wansong, Ye, Yunbin
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 23.12.2022
• Subjects: Animals; Antineoplastic Agents; CAR-T cells; CCL19; Cell Line, Tumor; Chemokine CCL19 - metabolism; gastric cancer; Heterografts; Humans; IL-15; Immunology; Immunotherapy; Interleukin-15 - metabolism; Ligands; NKG2D (natural killer group 2 member D); Receptors, Chimeric Antigen; Stomach Neoplasms - metabolism; Stomach Neoplasms - therapy; T-Lymphocytes; Zebrafish - metabolism; IL-15; CCL19; gastric cancer; NKG2D (natural killer group 2 member D); CAR-T cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.1002361

Chimeric antigen receptor (CAR) T cells have been proven effective for the treatment of B-cell-mediated malignancies. Currently, the development of efficient tools that supply CAR T cells for the treatment of other malignancies would have great impact. In this study, interleukin (IL)-15 and C-C motif chemokine ligand 19 (CCL19) were introduced into natural killer group 2D (NKG2D)-based CARs to generate 15×19 CAR T cells, which remarkably increased T-cell expansion and promoted the production of central memory T (T ) cells. 15×19 CAR T cells showed greater cytotoxicity to gastric cell lines than conventional CAR T cells and produced higher levels of IL-15 and CCL-19, which resulted in increased responder T cell chemotaxis and reduced expression of T cell exhaustion markers. A live zebrafish model was used for single-cell visualization of local cytotoxicity and metastatic cancers. Administration of 15×19 CAR T cells resulted in significant shrinking of gastric cancer xenograft tumors and expansion of 15×19 CAR T cells in zebrafish models. Taken together, these findings demonstrate that 15×19 CAR T cells are highly efficient in killing gastric cancer cells, are effective to avoid off-target effects, and migrate to local and metastatic sites for long-term surveillance of cancers.