Engineering TAG-72 and CD30 CAR-T Cells for T Cell Malignancies

T cell malignancies represent a broad, highly heterogeneous subset of lymphomas with poor prognosis. Chimeric antigen receptor (CAR)-T cell therapy holds great promise in treating B cell lymphoma and multiple myeloma. However, understanding its efficacy in treating T cell lymphoma remains challenging, primarily due to the lack of tumor-specific targets and intra-tumor heterogeneity. In this proof-of-concept study, we developed and characterized three distinct CAR-T cells targeting tumor-associated glycoprotein 72 (TAG-72), C-C chemokine receptor type 4 (CCR4) and tumor necrosis factor receptor CD30 respectively and assessed their anti-tumor efficacy against T cell malignancies in vitro. TAG-72 and CD30 CAR-T cells each demonstrated comparable expansion potential and eliminated tumor cells expressing their respective target antigens. Subsequently, we explored the advantages of targeting two antigens through the pooling of these CAR-T cells. In instances where target antigen expression was low (as determined by flow cytometry), dual targeting of TAG-72 and CD30 was able to elicit cytotoxic function. These findings define TAG-72 and CD30-targeting CAR-T cells as a promising strategy against T cell malignancies and highlight the potential of dual or combination CAR-T cell therapies for this aggressive disease.