Epigenetic Therapy as a Primer for Immunotherapy

DNA hypomethylating agents (HMAs) are at the forefront of epigenetic modulators for cancer treatments. As single agents, their efficacy is mainly appreciated in hematological studies prompting the development of second-generation DNA methylation inhibitors and drug delivery avenues. One of the mechanisms by which HMAs induce anti-tumor effects is by increasing tumor immunogenicity, highlighting its clinical use combined with immune checkpoint blockade (ICB). Despite extensive in vivo preclinical models across various solid tumor types demonstrated enhanced anti-tumor responses combining HMAs and ICB than either mono treatment. However, the challenge remains in achieving similar effectiveness in solid tumors as single agents or in combination in the clinics. This thesis explores the effects of HMAs through a two-pronged approach. First, we tested the clinical efficacy of combining CC-486 (an oral HMA) and durvalumab ICB (PD-L1 antibody) in selected solid tumors. Treatments did not demonstrate robust pharmacodynamic or clinical activity. However, findings from the study should inform continued drug development efforts using these agents. Second, we characterized the effects of HMAs in primary human CD8+ T-cells. We demonstrate that low dose decitabine treatments during ex vivo human T-cell expansion results in enhanced CD8+ T-cell activation and cytolytic effector function. Thus, providing additional support for using HMAs as a therapeutic strategy to boost anti-tumor immune response.Ph.D