Abstract
Treatment resistance remains a leading cause of acute leukemia-related deaths. Thus, there is an unmet need to develop novel approaches to improve outcome. New immune-based therapies with chimeric antigen receptor (CAR) T cells, bi-specific T cell engagers (BiTEs), and immune checkpoint blockers (ICBs) have emerged as effective treatment options for chemoresistant B cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML). However, many patients show resistance to these immune-based approaches. This review describes crucial lessons learned from immune-based approaches targeting high-risk B-ALL and AML, such as the leukemia-intrinsic (e.g., target antigen loss, tumor heterogeneity) and -extrinsic (e.g., immunosuppressive microenvironment) mechanisms that drive treatment resistance, and discusses alternative approaches to enhance the effectiveness of these immune-based treatment regimens.