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 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 v beta (TCRv beta) 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 TCRv beta family members were designed and validated. Our results demonstrate that TCRv beta-family-specific CARTs (TCRv beta-CARTs) recognize and kill TCRv beta-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 TCRv beta family. Furthermore, TCRv beta-CARTs eliminated the dominant malignant TCRv beta clone in 2 patient samples. Finally, in immunodeficient mice, TCRv beta-CARTs eradicated malignant cells in a TCRv beta-dependent manner. Importantly, the nontargeted TCRv beta families were spared in all cases. Thus, TCRv beta-CART therapy provides a potential option for high-precision treatment of PTCL with limited healthy T-cell depletion.

Automated summary

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies with ineffective treatment options and high relapse rates. Chimeric antigen receptor T-cell (CART) therapy has shown success in certain hematologic malignancies and presents a potential treatment option for PTCLs. Our study focuses on developing a CART platform specific to a given T-cell receptor v beta (TCRv beta) family, aiming to selectively target malignant cells while preserving healthy T cells. Our results demonstrate that TCRv beta-family-specific CARTs effectively kill TCRv beta-expressing target cells and eliminate the dominant malignant clone in patient samples, offering a high-precision treatment option for PTCL with limited healthy T-cell depletion.