**17. Connecting epigenetic modulation with immunotherapy**

Over In the past two decades, the FDA approval of various DNA methyltransferase inhibitors, collectively called DNA HMAs, and histone deacetylase inhibitors (HDACi) has brought epigenetic therapy to the forefront of cancer therapies. However, the benefits of epigenetic therapy are mainly restricted to the treatment of hematological malignancies. Thus, combination strategies with standard chemotherapy and targeted therapy approaches can be considered. A recent study involving advanced NSCLC patients revealed that patients after receiving low-dose epigenetic therapy entered a trial for immune checkpoint therapy. Approximately 20% of the patients responded to the immune checkpoint therapy alone, passing 24 weeks without progression, with most achieving high-grade RECIST criteria responses [122]. This is an astounding result for immunotherapy in NSCLC.

All 5 patients who had received the prior epigenetic therapy passed the 24-week point without progression with subsequent immune checkpoint therapy and three of these developed high-grade partial RECIST criteria responses that have all been durable over 2.5 years [123, 124]. Moreover, findings to date, support the hypothesis that there may be extraordinary potential for combined epigenetic and immunotherapy to increase the frequency of durable responses for immune checkpoint therapy in not only NSCLC but also other common tumor types.
