Have CARs stalled for non–B-cell malignancies? Where are we, and where are we going?

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of B-cell malignancies, but similar success in T-cell and myeloid leukemias has remained elusive due to unique biological and logistical barriers. T-cell acute lymphoblastic leukemia poses challenges such as fratricide, product contamination, and profound immunosuppression from T-cell aplasia. Gene editing, protein expression blockers, and antigen selection strategies have been employed to mitigate these risks, while allogeneic CAR T-cell platforms offer rapid deployment but carry risks of graft-versus-host disease and immune rejection. Early-phase trials targeting CD5 and CD7 have demonstrated promising response rates, particularly with gene-edited or bicistronic constructs, although toxicities and the need for consolidative hematopoietic stem cell transplantation remain significant hurdles. Similarly, CAR T-cell therapy for acute myeloid leukemia faces the dual obstacles of antigen nonspecificity and a highly immunosuppressive tumor microenvironment. Multiantigen targeting, logic-gated designs, and epitope editing have emerged to improve specificity and safety. Novel approaches to overcome the immunosuppressive milieu include checkpoint blockade and cytokine pathway modulation. Allogeneic and "off-the-shelf" CAR T-cell products are being developed to address manufacturing challenges in patients with rapidly progressive disease. Collectively, these advances highlight the potential of cellular therapies in high-risk leukemias and underscore the importance of continued innovation to improve outcomes in these historically treatment-refractory populations. Using a real-world case, we highlight the major challenges and innovative strategies shaping CAR T-cell therapy for T-cell acute lymphoblastic leukemia and acute myeloid leukemia.