Targeting Immune Signaling Checkpoints in Acute Myeloid Leukemia

Abstract

The modest successes of targeted therapies along with the curative effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) in acute myeloid leukemia (AML) stimulate the development of new immunotherapies. One of the promising methods of immunotherapy is the activation of immune response by the targeting of negative control checkpoints. The two best-known inhibitory immune checkpoints are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 receptor (PD-1). In AML, PD-1 expression is observed in T-cell subpopulations, including T regulatory lymphocytes. Increased PD-1 expression on CD8+ T lymphocytes may be one of the factors leading to dysfunction of cytotoxic T cells and inhibition of the immune response during the progressive course of AML. Upregulation of checkpoint molecules was observed after alloHSCT and therapy with hypomethylating agents, pointing to a potential clinical application in these settings. Encouraging results from recent clinical trials (a response rate above 50% in a relapsed setting) justify further clinical use. The most common clinical trials employ two PD-1 inhibitors (nivolumab and pembrolizumab) and two anti-PD-L1 (programmed death-ligand 1) monoclonal antibodies (atezolizumab and durvalumab). Several other inhibitors are under development or in early phases of clinical trials. The results of these clinical trials are awaited with great interest in, as they may allow for the established use of checkpoint inhibitors in the treatment of AML.

Keywords: acute myeloid leukemia; immunotherapy; programmed cell death protein 1 receptor/ programmed death-ligand 1 (PD-1/PD-L1) signaling.

Figure 1

(a) The regulation of antileukemic immune response; the activation of an immune response requires two signals. The first is responsible for the specific recognition of antigen (peptide) located in the great groove of the major histocompatibility complex (MHC) by the T-cell receptor (TCR). The second is the costimulatory signal that is transmitted by the interaction of CD28 and B7 molecules. These signals are regulated by many negative receptors including the lymphocyte-activation gene 3 (LAG3), OX40, programmed cell death protein 1 receptor (PD-1), CD43 as well as T-cell immunoglobulin domain and mucin domain 3 (TIM3) on the T cell that interacts with ligands on acute myeloid leukemia (AML) blasts, i.e., CD47, programmed death-ligand 1 (PD-L1) and Cytotoxic T-lymphocyte Antigen-4 (CTLA-4). (b) The restoration of antileukemic immune response by the targeting of the negative control checkpoints. In order to restore the antileukemic immune response, two inhibitory immune checkpoint molecules might be targeted by treatment with specific monoclonal antibodies directed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4), ipilimumab, and the programmed cell death protein 1, nivolumab and pembrolizumab as well as PD-L1, atezolizumab and durvalumab.

Figure 2

The numbers of active clinical trials for checkpoints inhibitors in acute myeloid leukemia.