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.
Highlights
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by heterogeneous clinical outcomes due to underlying molecular and cytogenetic architectures [1, 2]
Another cancer/testis antigens (CTAs) termed as preferentially expressed antigen in melanoma (PRAME) whose expression is primarily upregulated by DNA demethylation and its expression has been associated with favorable outcomes in leukemias including AML [52]
An independent study showed that both decitabine and guadecitabine increased programmed death-1 (PD-1), programmed death ligand1 (PD-L1), and cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) expression in a panel of eight hematological cancer cell lines including AML [87]. These findings suggest that resistance to hypomethylating agents (HMAs) in AML and MDS patients may be due to upregulated expression of immune checkpoint molecules, leading to exhaustion of CTLs and incomplete clearance of leukemia cells
Summary
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by heterogeneous clinical outcomes due to underlying molecular and cytogenetic architectures [1, 2]. Phase I and II clinical trials have assessed ICB therapy based on programmed death-1 (PD-1) and cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) inhibition but they have yielded modest clinical efficacy [12] These underscore the unmet need to enhance the efficacy of immunotherapy with other agents for AML and MDS treatments. The hypomethylating agents (HMAs) 5-azacytidine (azacitidine) and 5-aza-2’-deoxycytidine (decitabine) are cytidine nucleoside analogs approved for the treatment of AML and MDS patients. These HMAs mimic cytosine to incorporate into DNA during cellular replication, forming a scaffold that traps DNMTs for proteasomal degradation. For extended information of azacitidine combination with immunotherapy for the treatment of AML and MDS patients, readers are directed to a recent review by Daver et al [43]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
