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

Abstract

Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4⁺ and CD8⁺ T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.

Keywords: acute myeloid leukemia; cancer vaccine; chimeric antigen receptor-engineered (CAR)-T cell therapy; hypomethylating agents; immune checkpoint; myelodysplastic syndromes.

Figure 1

Chemical structure of decitabine and guadecitabine. Guadecitabine is a dinucleotide of decitabine (in blue) and deoxyguanosine (in green) joined by a phosphodiester bond.

Figure 2

Synergism of decitabine or guadecitabine with antileikemic immune cells and engineered T cells, and depletion of immunosuppressive cells in AML or MDS microenviroment. (A) DC/AML vacinne combined with decitabine or guadecitabine treatment induces leukemia-specific immunity; (B) Decitabine potentiates infused NK cells’ antileukemia activity by upregulating ligands for NKG2D and DNAM-1 immunoactivating receptors on NK cells. Decitabine combined with anti-CD33 mAb also augments the expression of NKG2D ligands in AML cells; (C) Upregulation of CTA expression such as NY-ESO-1 by decitabine or guadecitabine treatment synergizes with NY-ESO-1 cancer vaccine treatment; (D) Combination of decitabine or guadecitabine with novel immune checkpoint blockade therapy such as anti-TIGIT therapeutic antibody to circumvent resitance of AML or MDS cells to either hypomethylating agent; (E) Potential synergsim of decitabine or guadecitabine with anti-CD123 therapeutic antibody (e.g. tagraxofusp) to induce antileukemic immunity; (F) Decitabine treatment synergizes with CD123 CAR-T cells against AML cells; (G) Potential synergism of decitabine or guadecitabine with WT-1 specific TCR-T cells. ADCC: Antibody-dependent cellular cytotoxicity; AML: Acute myeloid leukemia; CAR-T: Chimeric antigen receptor-engineered T cell; CTA: Cancer/testis antigen; DC: Dendritic cell; DNAM-1: DNAX accessory molecule-1; ICR: Immune checkpoint receptor; ICRL: Immune checkpoint receptor ligand; mAb: Monoclonal antibody; MDS: Myelodysplastic syndromes; MDSC: Myeloid-derived suppressor cell; MHC: Major histocompatibility complex; NK: Natural killer; NKG2D: Natural killer group 2D; TCR: T cell receptor; TCR-T: T cell receptor-engineered T cell; TIGIT: T-cell immunoreceptor with Ig and ITIM domains; WT1: Wilms’ tumor 1. Upward arrow denotes upregulated expression, increased CTA presentation, or induced apoptosis of MDSCs.