A Review of Efficacy and Safety of Checkpoint Inhibitor for the Treatment of Acute Myeloid Leukemia

Abstract

Immune checkpoint inhibitors (ICIs) as positive modulators of immune response have revolutionized the treatment of cancer and have achieved impressive efficacy in melanoma and numerous solid tumor malignancies. These agents are being investigated in acute myeloid leukemia (AML) to further enhance response rate as induction therapy and to improve relapse-free survival (RFS) post chemotherapy and bone marrow transplantation. PD-1 and CTLA-4 are the two most actively investigated checkpoint receptors, which play a role in different stages of anti-tumor immune response. This study reviews data from ongoing phase I, II clinical trials evaluating PD-1 and CTLA-4 inhibitors on AML patients and discusses especially efficacy and adverse events as well as prospects of these drugs in treating AML. Single anti-PD-1 monoclonal antibody infusion shows rather modest clinical efficacy. While combinations of PD-1 inhibitor with hypomethylating agents (HMAs) represent encouraging outcome for relapsed/refractory (R/R) AML patients as well as for elderly patients as first-line therapy option. Adding PD-1 inhibitor to traditional induction therapy regimen is also safe and feasible. CTLA-4 inhibitor ipilimumab exhibits specific potency in treating relapsed AML patients with extramedullary disease in later post-transplantation stage. In terms of side effects, irAEs found in these trials can mostly be appropriately managed with steroids but are occasionally fatal. More rationally designed combinational therapies are under investigation in ongoing clinical trials and will further advance our understanding of checkpoint inhibitors as well as lead us to the most appropriate application of these agents.

Keywords: acute myeloid leukemia; checkpoint inhibitor; efficacy; immunotherapy; safety.

Figure 1

An illustration of PD-1/PD-L1 mediated immune tumor response. (A) PD-1 is a co-inhibitory molecule expressed on T cell, B cells, and myeloid cells. Binding of PD-1 to its B7 family of ligands PD-L1 on tumor cells results in suppression of proliferation and immune response of T cell, which are described as the “exhaustion” state of T cell. Activation of PD-1/PD-L1 signal pathway serves as a major mechanism of immune evasion by tumor cells. (B) Antibody blockade of PD-1 and PD-L1 reverses this process and enhances anti-tumor immune response. TCR, T-cell receptor; MHC, major histocompatibility complex; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1.

Figure 2

T cell activation regulated by CTLA-4 and CD28. (A) Simultaneous recognition of a specific major histocompatibility complex (MHC)–peptide complex by the T cell receptor (TCR) and of CD80/CD86 by the co-stimulatory receptor CD28 results in T cell activation. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a CD28 homologue expressed on the surface of T lymphocytes with higher affinity for CD80/CD86. When CTLA-4 competitively binds to CD80/CD86, signal 2 required for T cell activation reduces, which eventually leads to T cell anergy. (B) The blockade of CTLA-4 signaling restores signal 2 in response to binding of CD28 with CD80/CD86 thus promoting T cell activation and proliferation.