Immune escape and immunotherapy of acute myeloid leukemia

Abstract

In spite of the recent approval of new promising targeted therapies, the clinical outcome of patients with acute myeloid leukemia (AML) remains suboptimal, prompting the search for additional and synergistic therapeutic rationales. It is increasingly evident that the bone marrow immune environment of AML patients is profoundly altered, contributing to the severity of the disease but also providing several windows of opportunity to prompt or rewire a proficient antitumor immune surveillance. In this Review, we present current evidence on immune defects in AML, discuss the challenges with selective targeting of AML cells, and summarize the clinical results and immunologic insights from studies that are testing the latest immunotherapy approaches to specifically target AML cells (antibodies, cellular therapies) or more broadly reactivate antileukemia immunity (vaccines, checkpoint blockade). Given the complex interactions between AML cells and the many components of their environment, it is reasonable to surmise that the future of immunotherapy in AML lies in the rational combination of complementary immunotherapeutic strategies with chemotherapeutics or other oncogenic pathway inhibitors. Identifying reliable biomarkers of response to improve patient selection and avoid toxicities will be critical in this process.

Figure 1. The pathologic immune microenvironment of acute myeloid leukemia.

The illustration summarizes known leukemia-intrinsic and -extrinsic immune evasion mechanisms. As described in the main text, AML blasts can reduce their expression of antigen presentation molecules, overexpress inhibitory T cell ligands (including PD-L1, Gal-9, and others), and release in the bone marrow niche reactive oxygen species (ROS), indoleamine 2,3-dioxygenase (IDO), arginase (Arg), and extracellular vesicles (EVs). This, in turn, can inhibit the cytotoxic function of T and NK cells, drive effector T cell (Teff) exhaustion and apoptosis, induce regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and promote the switch of macrophages from M1 to suppressive M2 phenotype.

Figure 2. Bispecific antibody formats.

Schematic summary of some of the strategies that are being tested to link antigen-binding fragments (Fabs) of two or more monoclonal antibodies with different specificities. Under each construct are provided some examples of bispecifics of that class in advanced clinical development (see also Table 2).