Title:Immunomodulatory Drugs: Immune Checkpoint Agents in Acute Leukemia
VOLUME: 18 ISSUE: 3
Author(s):Hanna A. Knaus, Christopher G. Kanakry, Leo Luznik and Ivana Gojo
Affiliation:Cancer Research Building I, Room 346, 1650 Orleans Street, Baltimore, MD 21287
Keywords:Acute lymphoblastic leukemia, acute myeloid leukemia, co-inhibitory receptor, immune checkpoint pathway, immune
evasion, immunotherapy, monoclonal antibody, T cells.
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.
