Immune-Based Therapies in Acute Leukemia

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.

Keywords: CAR-T cell therapy; acute lymphoblastic leukemia; acute myeloid leukemia; bi-specific T cell engagers; immune checkpoint blockade; immune-based therapy.

Figure 1.. Intrinsic and extrinsic regulators of B-ALL-targeting CAR-T and BiTE therapy.

CAR-T and BiTE therapy targeting CD19⁺ B-ALL rely on effective T cell function to exert antileukemic function. Multiple extrinsic regulatory mechanisms can potentially impact antileukemic T cell function, including hematopoietic (e.g. MDSCs, Tregs), non-hematopoietic (e.g. vascular and perivascular niche) and biochemical (e.g. hypoxia) factors. CAR-T and BiTE therapy escape may be driven by intrinsic mechanisms, such as the existence of CD19- B-ALL blasts prior to therapy, leukemic lineage switching and target antigen reduction. In addition, extrinsic mechanisms such as T cell exhaustion, insufficient CAR-T expansion, antigen masking by CAR-transduced B-ALL blasts, antigen loss via trogocytosis, and a protective leukemic niche may all promote resistance to immune-based therapies.

Figure 2.. Immune-based approaches for the treatment of AML

AML blasts express cell surface molecules that can be targeted by CAR-T cells or BiTE. AML cell surface molecules can be targeted individually, by a single-specificity CAR-T cell, or in combination, by dual-specificity CAR-T cells. BiTE can be used to connect CD3⁺ T cells to AML surface molecules to induce killing of AML blasts. The bone marrow vascular niche secretes CXCL12, which binds CXCR4 on AML blasts and mediates homing of leukemic cells to the bone marrow. This axis can be blocked by CXCR4 inhibitors. CSF1R⁺ cells in the AML microenvironment support AML growth, and can be targeted by CSF1R inhibitors.