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.

Fatty acid synthase inhibitor orlistat impairs cell growth and down-regulates PD-L1 expression of a human T-cell leukemia line

“…[52][53][54] Similar to what observed in other malignancies, PD-L1 expression has been inconstantly detected on human AML cells. 55 Beside its critical role in maintaining an immunosuppressive tumor microenvironment by impairing T-cell mediated anti-tumor responses, 56 PD-L1 mediates also critical cell-intrinsic signals which regulate immune-independent tumor growth and metabolism, 57 while mediating resistance to chemotherapeutic agents. 58 Therefore, the decrease of PD-L1 expression mediated by orlistat can potentially reduce the tumor immune-pathogenesis while contributing to the inhibitory effect on tumor cell growth potential and metabolism.…”

Recent developments and future challenges in immune checkpoint inhibitory cancer treatment

“…The first clinical trials using anti-LAG3 antibodies in cancer patients are underway [50]. Other potential targets for therapeutic inhibition are BTLA, CD160, TIM3, CD244, TIGIT, and CD200R [51][52][53].…”

T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients

“…Although promising, it should be noted that single blockade of one inhibitory pathway is unlikely to accomplish an optimal anti-leukemia immune response. Leukemia may use a variety of inhibitory pathways to evade immune attack (21,22,26,27) and inhibition of one negative receptor may cause upregulation of others. Strategies combining blockade of multiple immune regulators are appealing.…”