RÉSUMÉ
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated with poor prognosis due to ineffective treatment options and high rates of relapse. The success of chimeric antigen receptor T-cell (CART) therapy for certain hematologic malignancies makes it an attractive treatment option for PTCLs. However, shared expression of potential target antigens by both malignant and healthy T cells poses a challenge. Current prospective CART approaches cause a high degree of on-target, off-tumor activity, resulting in fratricide during CART expansion, depletion of healthy T cells in vivo, and immune compromise in the patient. To limit off-tumor targeting, we sought to develop a CART platform specific for a given T-cell receptor vß (TCRvß) family that would endow CAR-modified T cells with the ability to mediate lysis of the clonal malignant population while preserving the majority of healthy T cells. Here, CAR constructs specific for multiple TCRvß family members were designed and validated. Our results demonstrate that TCRvß-family-specific CARTs (TCRvß-CARTs) recognize and kill TCRvß-expressing target cells. This includes specific self-depletion of the targeted cell subpopulation in the CART product and lysis of cell lines engineered to express a target TCRvß family. Furthermore, TCRvß-CARTs eliminated the dominant malignant TCRvß clone in 2 patient samples. Finally, in immunodeficient mice, TCRvß-CARTs eradicated malignant cells in a TCRvß-dependent manner. Importantly, the nontargeted TCRvß families were spared in all cases. Thus, TCRvß-CART therapy provides a potential option for high-precision treatment of PTCL with limited healthy T-cell depletion.