Recombination of a dual-CAR-modified T lymphocyte to accurately eliminate pancreatic malignancy

• Published in: Journal of hematology and oncology Vol. 11; no. 1; p. 102
• Main Authors: Zhang, Erhao, Yang, Peiwei, Gu, Jieyi, Wu, Heming, Chi, Xiaowei, Liu, Chen, Wang, Ying, Xue, Jianpeng, Qi, Weiyan, Sun, Qingbo, Zhang, Shengnan, Hu, Jialiang, Xu, Hanmei
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13-08-2018; BioMed Central; BMC
• Subjects: Antigen (tumor-associated); Antigens; Antitumor agents; Cancer immunotherapy; Cancer therapies; Carcino-embryonic antigen; Carcinoembryonic antigen; Care and treatment; Chimeric antigen receptors; Clinical trials; Cytokines; Cytotoxicity; Dual-receptor CAR; Embryos; Genetic aspects; Health aspects; Hematology; Immunotherapy; Lymphocytes; Lymphocytes T; Malignancy; Medical prognosis; Mesothelin; Metastasis; Oncology; Pancreatic cancer; Physiological aspects; Recombination; Signal transduction; Solid tumors; T cell receptors; T cells; Tumor cells; Tumors; Xenografts; China; Mesothelin; Dual-receptor CAR; Carcino-embryonic antigen; Cancer immunotherapy; Pancreatic cancer
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-018-0646-9

The therapeutic application of T cells endowing with chimeric antigen receptors (CARs) is faced with "on-target, off-tumor" toxicity against solid tumors, particularly in the treatment of the pancreatic cancer. To our best knowledge, the pancreatic cancer cell line AsPC-1 often highly expressed some distinct tumor-associated antigens, such as carcino-embryonic antigen (CEA) and mesothelin (MSLN). Therefore, in this research, we have characterized dual-receptor CAR-modified T cells (dCAR-T) that exert effective and safe cytotoxicity against AsPC-1 cells.
Based on the dual signaling pathway of wild T cells, we designed a novel dCAR diagram specific for CEA and MSLN, which achieved comparable activity relative to that of conventional CAR-T cells (CEA-CAR T or MSLN-CAR T). In this dCAR, a tandem construct containing two physically separate structures, CEA-CD3ζ and MSLN-4/1BB signaling domains were effectively controlled with tumor antigens CEA and MSLN, respectively. Finally, the activity of dCAR-T cells has been verified via in vitro and in vivo experiments.
In the presence of cognate tumor cells (AsPC-1) expressing both CEA and MSLN, dCAR-T cells exerted high anti-tumor activity relative to that of other single-receptor CAR-T cells bearing only one signaling pathway (e.g., Cζ-CAR and MBB-CAR). In a xenograft model, dCAR-T cells significantly inhibited the growth of AsPC-1 cells yet no effect on the growth of non-cognate tumor cells. Furthermore, the released cytokines and T cell persistence in mice were comparable with that of conventional CAR-T cells, obtaining specific and controllable cytotoxicity.
A novel type of CAR-T cells, termed dCAR-T, was designed with specific activities, that is, significant cytotoxicity for two antigen-positive tumor cells yet no cytotoxicity for single antigen-positive tumor cells. Dual-targeted CAR-T cells can be precisely localized at the tumor site and can exert high cytotoxicity against tumor cells, alleviating "on-target, off-tumor" toxicity and enabling accurate application of CAR-T cell therapy.