Chimeric antigen receptor T cell (CAR-T) therapy continues to be a powerful approach for treating relapsed-refractory hematological malignancies. Despite ongoing clinical success patients remain resistant to long-term benefits of CAR-T therapy. While there have been profound successes using CAR-T cells to target B cell malignancies, targeting T cell leukemias remain challenging as many of the target antigens on the cancer cells are shared with healthy T cells.
Work out of the Carl June laboratory, one of the pioneers of CAR-T therapy, has built a T cell-specific CAR-T cell with the ability to exploit chemokine receptor expression by subtypes of T cells to selectively target T cell leukemia. CCR4 is often expressed on leukemic cells in cutaneous T-cell lymphoma (CTCL). Clinical trials using mogamulizumab, a humanized monoclonal antibody against CCR4, show delayed disease progression with limited ability to promote long-term remission in CTCL. The June laboratory created a CCR4-CAR-T cell comprised of the antigen recognition domains of mogamulizumab. They found in reductionist and preclinical models that CCR4-CAR-T cells could effectively ablate tumor promoting Th2 and Tregs, while sparing anti-tumor CD8 cytolytic T cells and Th1 T cells. Furthermore, CCR4-CAR-T cells induced superior antitumor efficacy and long-term remission in mice engrafted with T cell lymphoma cells, suggesting that CCR4 could be an effective target to improve efficacy. These data suggest alternative chemokine and chemokine receptor pathways that can be exploited therapeutically.
Blood Advances 2023. Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma.
[2023 Jul 25;7(14):3416-3430. doi: 10.1182/bloodadvances.2022008327]