Immunomodulatory Drugs: Immune Checkpoint Agents in Acute Leukemia

Abstract

Intrinsic immune responses to acute leukemia are inhibited by a variety of mechanisms, such as aberrant antigen expression by leukemia cells, secretion of immunosuppressive cytokines and expression of inhibitory enzymes in the tumor microenvironment, expansion of immunoregulatory cells, and activation of immune checkpoint pathways, all leading to T cell dysfunction and/or exhaustion. Leukemic cells, similar to other tumor cells, hijack these inhibitory pathways to evade immune recognition and destruction by cytotoxic T lymphocytes. Thus, blockade of immune checkpoints has emerged as a highly promising approach to augment innate anti-tumor immunity in order to treat malignancies. Most evidence for the clinical efficacy of this immunotherapeutic strategy has been seen in patients with metastatic melanoma, where anti-CTLA-4 and anti-PD-1 antibodies have recently revolutionized treatment of this lethal disease with otherwise limited treatment options. To meet the high demand for new treatment strategies in acute leukemia, clinical testing of these promising therapies is commencing. Herein, we review the biology of multiple inhibitory checkpoints (including CTLA-4, PD-1, TIM-3, LAG-3, BTLA, and CD200R) and their contribution to immune evasion by acute leukemias. In addition, we discuss the current state of preclinical and clinical studies of immune checkpoint inhibition in acute leukemia, which seek to harness the body's own immune system to fight leukemic cells.

Keywords: Acute lymphoblastic leukemia; T cells.; acute myeloid leukemia; co-inhibitory receptor; immune evasion; immune checkpoint pathway; immunotherapy; monoclonal antibody.

Fig. (1). Selected Immune Checkpoint Receptors and their Respective Ligands

Tumors co-opt immune checkpoint pathways as a critical mechanism of immune evasion. Immune checkpoints are initiated by ligand-receptor interactions and inhibit T cell activation and proliferation. Fig. (1) shows selected immune checkpoint receptors including BTLA (B- and T-lymphocyte attenuator) that binds to its ligand HVEM (herpes virus entry mediator), CD200R that engages with CD200, CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) that binds the B7 molecules (CD80 and CD86), LAG-3 (lymphocyte activation gene 3) that binds to the MHC complex, PD-1 (programmed cell death-1) that engages with PD-L1 or PD-L2, and TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3) that binds galectin 9 on the antigen presenting cell or tumor cell.