Challenges and Solutions to Implementation of Chimeric Antigen Receptor Therapies in Acute Myeloid Leukemia

The field of acute myeloid leukemia (AML) therapeutics has seen significant progress with respect to the development of targeted agents for specific mutational subsets. However, outcomes for patients with high-risk AML remain dismal, and curative intent therapy is often challenging to administer in this population. AML is a highly plastic entity that employs a variety of mechanisms to circumvent immunosurveillance. In the recent decade, preclinical evidence for chimeric antigen receptor-T (CAR-T) and chimeric antigen receptor-natural killer (CAR-NK) therapies has gained traction in a variety of other hematologic malignancies, but the translation of these therapies to patients with AML has been limited. In this review, we discuss contemporary challenges to the clinical translation of cell-based therapeutics in AML. We underscore practical solutions to facilitating the clinical availability of novel cell-based therapies in AML. These solutions include widening the narrow therapeutic window through better myeloid-specific CAR target validation, developing multi-antigen or tandem CAR products, optimizing the immune repertoire and bone marrow niche in AML, and enhancing scalability of cell-based therapeutics such that patients in local communities can benefit from ongoing efforts. These strategies may help improve the translational success of CAR-T and CAR-NK therapies in AML in the coming years.