Chimeric antigen receptor T cells for acute myeloid leukemia

Abstract

AbstractThe use of T cells expressing chimeric antigen receptors (CARs) that can target and eliminate cancer cells has revolutionized the treatment of B‐cell malignancies. In contrast, CAR T cells have not yet become a routine treatment for myeloid malignancies such as acute myeloid leukemia (AML) or myeloproliferative neoplasms (MPNs). For these disease entities, allogeneic hematopoietic cell transplantation (allo‐HCT) relying on polyclonal allo‐reactive T cells is still the major cellular immunotherapy used in clinical routine. Here, we discuss major hurdles of CAR T‐cell therapy for myeloid malignancies and novel approaches to enhance their efficacy and reduce toxicity. Heterogeneity of the malignant myeloid clone, CAR T‐cell induced toxicity against normal hematopoietic cells, lack of long‐term CAR T‐cell persistence, and loss or downregulation of targetable antigens on myeloid cells are obstacles for successful CAR T cells therapy against AML and MPNs. Strategies to overcome these hurdles include pharmacological interventions, for example, demethylating therapy to increase target antigen expression, multi‐targeted CAR T cells, and gene‐therapy based approaches that delete the CAR target antigen in the hematopoietic cells of the recipient to protect them from CAR‐induced myelotoxicity. Most of these approaches are still in preclinical testing but may reach the clinic in the coming years. In summary, we report on barriers to CAR T‐cell use against AML and novel therapeutic strategies to overcome these challenges, with the goal of clinical treatment of myeloid malignancies with CAR T cells.