Emerging Immunotherapy for Acute Myeloid Leukemia

Abstract

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11-67% CR rates with 13-78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10-36% CR rates with 7-24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.

Keywords: acute myeloid leukemia (AML); bispecific T-cell engager (BiTE); chimeric antigen receptor (CAR); dual-affinity retargeting (DART); immune check-point inhibitor (ICI); trispecific killer cell engager (TriKE).

Figure 1

The scheme of immune checkpoint molecules associated with anti-leukemic immunity. Direct cytotoxicity in leukemic cells is attenuated by the binding of programmed cell death-1 (PD-1) on T cells and programmed cell death-ligand 1 (PD-L1) on cancer cells. T-cell activation via B7 family molecules on dendritic cells is canceled by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Phagocytic activity of macrophages is dampened by the “don’t eat me” signals of CD47 on leukemic cells. Lymphocyte activation gene-3 protein (LAG-3) expressed on T cells or natural killer cells inhibit the activity of CD4-positive T cells. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) has multiple inhibitory mechanisms such as attenuation of natural killer (NK) cell activity/stabilization of regulatory T cells by binding to galectin-9 and neutralizing the pro-inflammatory effect of HMGB1 and phosphatidylserine (PtdSer).

Figure 2

Potential immune targets being investigated in preclinical and early-phase trials. CAR consists of an antigen-recognizing extracellular domain and an intracellular signal domain(s). CAR-T or natural killer-targeting CD33, CLL-1, and pan-cancer antigen NKG2D have been evaluated in phase I trials. While bispecific T-cell engager (BiTE) and trispecific killer cell engager (TriKE) are composed of a single-chain variable fragment (scFv), dual-affinity retargeting (DART) is composed of two cross-linked variable fragments. Bispecific antibodies (BiTEs and DARTs) targeting CD33 and CD123 have been tested in early-phase trials. Gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate, has already been used in clinical practice.