Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes

Abstract

Immune checkpoint inhibitors, as single-agent therapy, have shown modest clinical efficacy in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). As has been successfully shown in other less immunogenic hematologic malignancies, rationally designed combination approaches may be more effective than single-agent checkpoint inhibitors, and may be the approach to pursue in AML/MDS. Hypomethylating agents (HMAs) such as azacitidine, while enhancing anti-tumor immune response, concurrently dampen immune response by upregulating inhibitory immune checkpoint molecule expression. Immune checkpoint molecule upregulation may be an important mechanism of azacitidine resistance. These findings have resulted in multiple clinical trials combining HMAs with immune checkpoint blockade. Clinical trial data have shown encouraging response rates and durable responses without resorting to stem cell transplant. In this review, we discuss preclinical data supporting the use of these agents in combination, and focus on clinical and correlative data emerging from numerous clinical trials investigating HMA-immune checkpoint inhibitor combinations in AML/MDS.

Fig. 1

Illustration of the effect of hypomethylating therapy on gene promoters. HMAs induce demethylation of methylated CpG islands of gene promoters regulating expression of several immune pathway-related genes including PD-L1, in tumor cells and PD-1 and CTLA-4 in T cells. Demethylation of these sites induces gene expression of PD-1 and CTLA-4 in T-cells, and PD-L1 in tumor cells. The expression of these co-inhibitory receptors leads to “exhausted” T cells with abrogation of anti-tumor response. At the same time HMA-induced demethylation has favorable effects on anti-tumor immunity including increased T-cell receptor and CD28 expression on T cells, increased expression of IFN-gamma viral defense genes, and enhanced tumor cell antigen and endoretroviral sequences (ERV) expression leading to activation of cellular antiviral response. Increased expression of PD-1/PD-L1 and CTLA-4 may be important mechanism of azacitidine resistance and potential targets for combinatorial approaches with immune check point inhibitors

Fig. 2

Immune check point inhibitors currently being tested in combination with azacitidine in ongoing clinical trials in AML/MDS are demonstrated in this figure. Important druggable targets include PD-1 (nivolumab, pembrolizumab) and CTLA-4 (ipilimumab, tremelimumab) receptors on T cells, PD-L1 (durvalumab, atezolizumab) on antigen-presenting and tumor cells, and inhibitor KIR (lirimumab) receptors on natural killer cells