The Latest Breakthroughs in Immunotherapy for Acute Myeloid Leukemia, with a Special Focus on NKG2D Ligands

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion of stem and myeloid progenitor cells. Immunotherapy has revolutionized the care for other cancers such as solid tumors and lymphomas, and has the potential to effectively treat AML. There has been substantial progress in the developments of immunotherapeutic approaches for AML over the last several years, including the development of antibodies that further increase the innate immunogenicity of leukemia cells by the inhibition of NKG2D ligand-particularly MICA and MICB-shedding, chimeric proteins such as IL-15 superagonist that expand natural killer (NK) cells, blockers of immunologic checkpoints such as NKG2A, and chemicals that indirectly increase expression of immune stimulatory proteins in leukemia stem cells. Furthermore, cellular therapies have been designed to enable alloreactive immunity by allogeneic NK cells or target leukemia antigens such as mutated NPM1. These immunotherapeutic approaches have demonstrated remarkable efficacies in preclinical studies and have successfully transitioned to early phase clinical trials, to establish safety and initial signal of clinical activity. Here, we briefly discuss some of the most recent and impactful developments in the AML immunotherapy field and provide our perspectives for the future directions of this exciting and new therapeutic opportunity.

Keywords: AML; NK cells; antibodies; immunotherapy.

Figure 1

Modalities of NKG2DL-based immunotherapy in AML. (a) Cellular therapies consisting of NK or T cells expressing the NKG2D ectodomain fused to cytoplasmic signaling domain(s). NKG2D-CAR recognize the whole NKG2D ligandome and induces potent T and NK cell antitumor reactivity, respectively. (b) Epigenetic compounds such as PARP/histone deacetylase (HDAC) inhibitors or hypomethylating agents (HMA) lead to substantial upregulation of surface NKG2DL expression and thus re-sensitize AML cells to NKG2D-mediated NK/T cell immunity or make them susceptible to NKG2DL-based targeted therapies. (c) Antibodies (Ab) and engineered antibody-like formats which bind to NKG2DL and engage CD16a on NK cells. An Ab which binds to the α-3 domain of MICA/B and thereby blocks their shedding from the tumor surface is currently evaluated in a clinical trial. Additionally, Fc-optimized NKG2D-Ig fusion proteins have been tested to induce ADCC against target cells which express any of the 8 NKG2DL and enhanced the anti-leukemic reactivity of NK cells. Similarly, an NKG2DxCD16a bispecific has been tested which consists of the NKG2D ectodomain fused to an anti-CD16a single chain variable fragment (scFv) and consequently displays higher affinity to the Fc receptor than Fc domains. This figure was created with BioRender.com.