Cancer immune evasion is achieved through multiple layers of immune mechanisms. Methylation of immune synapse genes is a crucial driver of tolerogenic immune landscapes and immune evasion in cancer. Notably, preclinical studies demonstrate the efficacy of demethylating agents to augment immunotherapy. This Moffitt technology is a diagnostic to predict response to immunotherapy based on the methylation status of immune synapse gene signature. This technology predicts a subset of patients with hypermethylated co-stimulatory genes (PC1high) will benefit from combination therapy of PD1 blockade with 5-azacitidine, while conversely, patients with hypermethylated immune checkpoint genes (PC2high) may be adversely impacted.
- FDA has approved nivolumab (Opdivo®) and pembrolizumab (Keytruda®) to treat patients with unresectable or metastatic solid tumors that have progressed following prior therapy, with no satisfactory alternative treatment options.
- FDA recently also approved Onureg® (azacitidine tablets), a DNA methyltransferase inhibitor, as continued treatment for adults in first remission with acute myeloid leukemia.
- Given negative preliminary findings from the phase II randomized clinical trial of oral 5-azacitidine plus pembrolizumab, patient selection may be crucial to overcome resistance to PD1 blockade.
- Clinically, a major advantages to the use of methylation status for patient selection is that epigenetic changes are heritable while the DNA is stable, and degradation is less likely in formalin-fixed paraffin-embedded tissues, and thus anticipated to be more robust than RNA-based or histology-based approaches.