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

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of cancers 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 but, due to the expression of potential target antigens by both malignant and healthy T cells, is challenging. Current prospective CART approaches cause a high degree of on-target, off-tumor activity resulting in fratricide, depletion of healthy T cells, and immune compromise in the patient. To limit off-tumor targeting, we sought to develop a CAR platform specific for a given TCRvb family that would endow 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 recognize and kill TCRvb family-expressing target cells. This includes specific self-depletion of the targeted TCRvb+ cell subpopulation in the CART product and lysis of cell lines engineered to express the target TCRvb family. Furthermore, TCRvb CAR T cells eliminated the dominant malignant TCRvb clone in two patient samples. Finally, in immunodeficient mice, TCRvb CAR T cells eradicated malignant cells in a TCRvb family-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.