T cell receptor β-chain-targeting chimeric antigen receptor T cells against T cell malignancies

Author:

Li Fanlin,Zhang Huihui,Wang Wanting,Yang Puyuan,Huang Yue,Zhang Junshi,Yan Yaping,Wang Yuan,Ding Xizhong,Liang Jie,Qi Xinyue,Li Min,Han Ping,Zhang Xiaoqing,Wang Xin,Cao Jiang,Fu Yang-XinORCID,Yang XuanmingORCID

Abstract

AbstractThe success of chimeric antigen receptor (CAR) T cells in treating B cell malignancies comes at the price of eradicating normal B cells. Even though T cell malignancies are aggressive and treatment options are limited, similar strategies for T cell malignancies are constrained by the severe immune suppression arising from bystander T cell aplasia. Here, we show the selective killing of malignant T cells without affecting normal T cell-mediated immune responses in vitro and in a mouse model of disseminated leukemia. Further, we develop a CAR construct that carries the single chain variable fragment of a subtype-specific antibody against the variable TCR β-chain region. We demonstrate that these anti-Vβ8 CAR-T cells are able to recognize and kill all Vβ8+malignant T cells that arise from clonal expansion while sparing malignant or healthy Vβ8T cells, allowing sufficient T cell-mediated cellular immunity. In summary, we present a proof of concept for a selective CAR-T cell therapy to eradicate T cell malignancies while maintaining functional adaptive immunity, which opens the possibility for clinical development.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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