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Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency

Gene Therapy volume 20, pages 970–978 (2013)Cite this article

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Abstract

Immunotherapy that is based on adoptive transfer of T lymphocytes, which are genetically modified to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens, has been demonstrated to be an efficient cancer therapy. Vascular endothelial growth factor receptor-1 (VEGFR-1), a vital molecule involved in tumor growth and angiogenesis, has not been targeted by CAR-modified T lymphocytes. In this study, we generated CAR-modified T lymphocytes with human VEGFR-1 specificity (V-1 CAR) by electroporation. V-1 CAR-modified T lymphocytes were demonstrated to elicit lytic cytotoxicity to target cells in a VEGFR-1-dependent manner. The adoptive transfer of V-1 CAR T lymphocytes delayed tumor growth and formation and inhibited pulmonary metastasis in xenograft models and such efficacies were enhanced by cotransfer of T lymphocytes that expressed interleukin-15 (IL-15). Moreover, V-1 CAR-modified T lymphocytes lysed primary endothelial cells and impaired tube formation, in vitro. These data demonstrated the antitumor and anti-angiogenesis ability of V-1 CAR-modified T lymphocytes. Our study provides the rationale for the clinical translation of CAR-modified T lymphocytes with VEGFR-1 specificity.

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Acknowledgements

We thank Professor Li Deng in Tissue engineering Institute, West China Medical School, West China Hospital and Professor Hua-Shun Li, the Second affiliated Hospital, Sichuan University, for the technical supports. This work is supported by National 973 Basic Research Program of China (Grants 2006CB504303 and 2010CB529900), the National 863 High Tech Foundation (Grants 2007AA021205 and 2006AA03Z356), the National Natural Science Foundation of China (Grants 81201789/H1611), the National Major Project (2009ZX09503-005), the Postdoctoral Foundation of China (Grants 2011M501306), and the Youth Research Foundation of Sichuan University (Grants 2082604154099).

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  1. State Key Laboratory of Biotherapy and Cancer Center, West China Medical School, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    W Wang, Y Ma, J Li, H-S Shi, L-Q Wang, F-C Guo, J Zhang, D Li, B-H Mo, F Wen, T Liu, Y-T Liu, Y-S Wang & Y-Q Wei

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Wang, W., Ma, Y., Li, J. et al. Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency. Gene Ther 20, 970–978 (2013). https://doi.org/10.1038/gt.2013.19

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