Identifying highly active anti-CCR4-CAR T cells for the treatment of T-cell lymphoma.

A challenge when targeting T cell lymphoma with chimeric antigen receptor (CAR) T cell therapy is that target antigens are often shared between T cells and tumor cells, resulting in fratricide between CAR T cells and on-target cytotoxicity on normal T cells. CC chemokine receptor 4 (CCR4) is highly expressed by many mature T-cell malignancies such as adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL) and has a unique expression profile on normal T cells. CCR4 is dominantly expressed by type-2 and type-17 helper T cells (Th2 and Th17), and regulatory-T cells (Treg) but it is rarely expressed by the other Th subsets and CD8+ cells. While fratricide in CAR T cells is generally thought to be detrimental to anti-cancer functions, in this study, we demonstrate anti-CCR4 CAR T cells specifically deplete Th2 and Treg T cells while sparing CD8+ and Th1 T cells. Moreover, fratricide enhances the percentage of CAR+ T cells in the final product. CCR4-CAR T cells were characterized by high transduction efficiency, robust T cell expansion, and rapid fratricidal depletion of CCR4 positive T cells during CAR transduction and expansion. Furthermore, mogamulizumab-based CCR4-CAR T cells induced superior anti-tumor efficacy and long-term remission in mice engrafted with human T-cell lymphoma cells. In summary, CCR4-depleted anti-CCR4 CAR T cells are enriched in Th1 and CD8+ T cells and possess high anti-tumor efficacy against CCR4-expressing T cell malignancies.