Immunotherapeutic Concepts to Target Acute Myeloid Leukemia: Focusing on the Role of Monoclonal Antibodies, Hypomethylating Agents and the Leukemic Microenvironment

Abstract

Intensive chemotherapeutic protocols and allogeneic stem cell transplantation continue to represent the mainstay of acute myeloid leukemia (AML) treatment. Although this approach leads to remissions in the majority of patients, long-term disease control remains unsatisfactory as mirrored by overall survival rates of approximately 30%. The reason for this poor outcome is, in part, due to various toxicities associated with traditional AML therapy and the limited ability of most patients to tolerate such treatment. More effective and less toxic therapies therefore represent an unmet need in the management of AML, a disease for which therapeutic progress has been traditionally slow when compared to other cancers. Several studies have shown that leukemic blasts elicit immune responses that could be exploited for the development of novel treatment concepts. To this end, early phase studies of immune-based therapies in AML have delivered encouraging results and demonstrated safety and feasibility. In this review, we discuss opportunities for immunotherapeutic interventions to enhance the potential to achieve a cure in AML, thereby focusing on the role of monoclonal antibodies, hypomethylating agents and the leukemic microenvironment.

Keywords: acute myeloid leukemia; hypomethylating agents; immunotherapy, monoclonal antibodies; microenvironment.

Figure 1

Hypomethylating agents (HMAs) and their role as immunomodulatory drugs in AML. HMAs possess both immuno-stimulatory, as well as immunosuppressive properties. They stimulate an immune response against AML blasts by increasing the expression of cancer testis antigens (e.g., NY-ESO-1 and MAGE-A), as well as important elements of the antigen-presenting machinery like the MHC I molecule and costimulatory molecules like ICAM1, as well as CD80 and CD86. On the other hand, HMAs can lead to immune escape of AML blasts through upregulation of immune checkpoints and their ligands, as well as regulatory T-cells. Combining the immunomodulatory effects of HMAs with other forms of immunotherapy holds the promise of a synergistic effect on the immune system. HMAs are currently combined with vaccines and drug-conjugated antibodies with the goal of increasing antigenicity and therefore AML blasts recognition and elimination by the immune system. Furthermore, combining HMA with checkpoint inhibitors might enhance the effect of checkpoint inhibitors in restoring immune surveillance. Lastly, combining HMAs with allo-HSCT or donor lymphocyte infusion is based on the hope that HMAs will enhance the graft versus leukemia effect (GVL) via enhanced antigenicity while limiting graft versus host disease (GVHD) by expansion of regulatory T-cells.