Cancer Therapy via a Combination of Epigenetic Modulation and Immune Modulation

In addition to the conventional forms of cancer therapy (chemotherapy, surgery, radiation), newer forms of therapy, including epigenetic modulation with DNA demethylating agents and HDAC inhibitors and therapies targeted at the immune system, are being investigated. We have discovered that epigenetic modulation alters tumor gene expression so as to induce an immune signature. Based on this finding and the known ability of demethylating agents to induce de novo expression of tumor-specific antigens, as well as a discovery that tumors induce immune checkpoint ligands to protect themselves from anti-tumor immune responses, we postulate that a combination of epigenetic modulation and blockade of immune checkpoint pathways, such as the PD-1 pathway, will provide a synergistic anti-tumor response. This postulate was tested by observing the clinical outcomes of advanced, chemotherapy refractory lung cancer patients treated with antibodies that block the PD-1 checkpoint pathway after their tumors progressed during epigenetic modulation. Three of four patients treated sequentially with epigenetic modulation followed by PD-1 pathway blockade developed objective clinical responses with dramatic tumor shrinkage. The fourth developed stable disease lasting >6 months. Taken together, these finding demonstrate an unexpected synergistic activity against cancer between epigenetic modulation and immune modulation.

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