Abstract IA12: Epigenetic therapy—potential efficacy for enhancing immune checkpoint therapy

Abstract

Abstract Despite the tremendous contribution made to date by immune checkpoint therapy to cancer management, most patients with the most common and deadliest forms of advanced cancer still do not receive durable benefit. Achieving manifest responses initially, understanding what predicts and contributes to long-term overall survival, and how to reverse initial or evolved resistance are all still major challenges to be addressed. Developing combinatorial approaches that may contribute to all of the above issues is a major goal, and epigenetic therapy is in play as one strategy for this purpose. Key specific points of the overall potential for the merits of combining this latter approach with immune checkpoint and other immunotherapies will be discussed in this presentation and include: 1) Critical steps in tumor immune evasion are under epigenetic control and can be reversed experimentally. There is evidence emerging that this also may be accomplished in patients and with epigenetic therapy drugs clinically available and in clinical trials such as DNA methyltransferase (DNMTis) and histone deactylase inhibitors (HDACis). The above steps for these drugs include restoration of tumor antigen presentation processes, restoration of tumor cell signaling for attraction of key antitumor subsets of immune cells, repulsion from tumors of key cells that promote immune tolerance, and repression of key oncogenic signaling pathways that otherwise suppress these above tumor immune attraction signals. 2) Key facets of immune tolerance inherent to signaling in immune cell subsets are under the control of epigenetic processes, and these too can be reversed by the types of drugs listed above, including T-cell and other immune cell exhaustion signaling, behavior of key ligands and receptors on immune cells critical for their migration to tumor cell sites and attack of cancer cells. Key experimental data for the above processes, coming from our own lab group and many collaborations within our participation in the Van Andel Institute – Stand Up To Cancer (VAI-SU2C) epigenetic therapy dream team, will be presented to support the hypotheses articulated above. Barriers to achieving efficacy of the approach, including which drugs will ultimately prevail, how to best sequence administration of the drugs, what cancer stages are most optimal for therapy institution, and what molecular parameters are promising for predicting efficacy, will also be discussed. Citation Format: Stephen B. Baylin. Epigenetic therapy—potential efficacy for enhancing immune checkpoint therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA12.