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

The 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 Vβ8⁻ T 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. Healthy T cells are polyclonal, while malignant T cells are developing via clonal expansion. Here authors show that T cell tumours could be eradicated by chimeric antigen receptor T cells targeting the T cell receptor (TCR) β-chain that is specific to malignant T cells, while healthy T cells using diverse TCR β-chains are spared. [ABSTRACT FROM AUTHOR]