Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia (AML) and enhances the immunogenicity of a dendritic cell/AML vaccine

Abstract

Acute myeloid leukemia (AML) is a lethal hematologic malignancy characterized by an immunosuppressive milieu in the tumor microenvironment (TME) that fosters disease growth and therapeutic resistance. Hypomethylating agents (HMAs) demonstrate clinical efficacy in AML patients and exert immunomodulatory activities. In the present study, we show that guadecitabine augments both antigen processing and presentation resulting in increased AML susceptibility to T cell-mediated killing. Exposure to HMA results in the activation of the endogenous retroviral pathway with concomitant downstream amplification of critical mediators of inflammation. In an immunocompetent murine leukemia model, guadecitabine negatively regulates inhibitory accessory cells in the TME by decreasing PD-1 expressing T cells and reducing AML-mediated expansion of myeloid derived suppressor cells. Therapy with guadecitabine results in enhanced leukemia-specific immunity as manifested by increased CD4 and CD8 cells targeting syngeneic leukemia cells. We have previously reported that vaccination with AML/dendritic cell fusions elicits the expansion of leukemia-specific T cells and protects against disease relapse. In the present study, we demonstrate that vaccination in conjunction with HMA therapy results in enhanced anti-leukemia immunity and survival. The combination of a novel personalized DC/AML fusion vaccine and an HMA has therapeutic potential, and a clinical trial investigating this combination is planned.

Case Report: Low-Dose Decitabine Plus Anti-PD-1 Inhibitor Camrelizumab for Previously Treated Advanced Metastatic Non-Small Cell Lung Cancer

“…Therefore, it was hypothesized that low-dose decitabine as an epigenetic drug could improve the efficacy of PD-1/PD-L1 antibodies. Currently, epigenetic drugs in combination with PD-1/PD-L1 antibodies have been studied for the treatment of lymphoma, acute myeloid leukemia, and myelodysplastic syndrome (4,(8)(9)(10), but there are few studies on their efficacy against solid tumors.…”

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes

“…Treatment of AML cells (THP-1) with guadecitabine resulted in increased expression of HLA-A2.1 with increased antigen presentation. In vivo model (mouse AML cells TIB-49 in C57BL/6J mice) treated with guadecitabine displayed T cells with reduced PD-1 levels but increased IFN-γ expression, as well as decrease in myeloid-derived suppressor cell (MDSC) populations ( 67 ). Personalized cancer vaccine was previously developed by the same research group whereby patient-derived AML cells fused with autologous DCs produced hybridoma ( i.e.…”

Dendritic Cell-Based Immunotherapy of Acute Myeloid Leukemia

“…This may indicate that DC vaccination can potentiate the response to subsequent treatment, an observation that has also been made in the solid tumor vaccine field [67,96]. Hypomethylating agents (HMAs), which are being increasingly applied in the frontline treatment of elderly AML patients, have also shown synergistic activity with DC vaccination; one of the mechanisms underlying this synergism involves reduction of PD-1 expression on T cells and inhibition of MDSCs [97]. A phase II randomized clinical trial ( identifier NCT01686334) is currently ongoing to evaluate the effectiveness of combined HMA treatment and WT1 mRNA-targeted DC vaccination.…”