TCRvβ-CART therapy mediates high precision targeting of malignant T-cell clones.

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 hematological 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 CAR T-cell 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 TCRvb 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 TCRvb family members were designed and validated. Our results demonstrate that TCRvb family-specific CAR T cells (TCRvb-CARTs) recognize and kill TCRvb-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 TCRvb family. Furthermore, TCRvb-CARTs eliminated the dominant malignant TCRvb clone in two patient samples. Finally, in immunodeficient mice, TCRvb-CARTs eradicated malignant cells in a TCRvb-dependent manner. Importantly, in all cases the non-targeted TCRvb families were spared. Thus, TCRvb-CART therapy provides a potential option for high-precision treatment of PTCL with limited healthy T-cell depletion.