2. Academic Validation
  3. Recombination of a dual-CAR-modified T lymphocyte to accurately eliminate pancreatic malignancy

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

  • J Hematol Oncol. 2018 Aug 13;11(1):102. doi: 10.1186/s13045-018-0646-9.
Erhao Zhang 1 2,  Peiwei Yang 1,  Jieyi Gu 1,  Heming Wu 3,  Xiaowei Chi 1,  Chen Liu 1,  Ying Wang 1,  Jianpeng Xue 1 4,  Weiyan Qi 1 4,  Qingbo Sun 1,  Shengnan Zhang 1,  Jialiang Hu 5 6,  Hanmei Xu 7 8 9
Affiliations

Affiliations

  • 1 The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
  • 2 Basic Medical Research Center, School of Medicine, Nantong University, Nantong, 226001, People's Republic of China.
  • 3 Jiangsu Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 211166, People's Republic of China.
  • 4 State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
  • 5 The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. haobo89@163.com.
  • 6 State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. haobo89@163.com.
  • 7 The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. 13913925346@126.com.
  • 8 State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. 13913925346@126.com.
  • 9 Nanjing Anji Biotechnology Co., Ltd, Nanjing, 210046, People's Republic of China. 13913925346@126.com.
PMID: 30103775 DOI: 10.1186/s13045-018-0646-9
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Cancer immunotherapy; Carcino-embryonic antigen; Dual-receptor CAR; Mesothelin; Pancreatic cancer.

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