Abstract 1740: Epigenetic reprogramming of the tumor microenvironment by entinostat increases tumor sensitivity to multivalent immunotherapy combinations with an IL-15 superagonist plus vaccine or immune checkpoint blockade
Authors: Hicks Kristin C. , Knudson Karin M. , Jones Frank R. , Ordentlich Peter , Rabizadeh Shahrooz , Wong Hing C. , Hodge James W. , Schlom Jeffrey , Gameiro Sofia R. 
Published: August 2018

Abstract
The clinical promise of cancer immunotherapy relies on the immune system recognizing and eliminating tumor cells identified as non-self. However, the tumor microenvironment (TME) can greatly impede a tumor targeted immune response via increasing immunosuppressive cells or hampering T and NK cell maturation, recruitment, and function through numerous pathways, including upregulation of immune checkpoints such as PD-L1. Hence, there is an unmet clinical need to develop effective therapeutic strategies that can reprogram the TME to restore tumor immune recognition and reverse immune evasion. We recently demonstrated that Entinostat, a class I histone deacetylase (HDAC) inhibitor, reverses tumor immune escape to T cell-mediated lysis. We hypothesize that the immune-mediated tumor elimination promoted by the IL-15/IL-15Rα superagonist ALT803 in combination with PD-L1 checkpoint blockade or a therapeutic adenoviral vaccine targeting CEA (Ad-CEA) will be augmented by the epigenetic reprograming of the TME induced by Entinostat. In preclinical studies, ALT803 has been shown to exhibit potent antitumor activity in multiple murine models of cancer through the expansion of NK and CD8+ T cells with high effector function. Here, we demonstrate that Entinostat increased extracellular expression of immune-relevant proteins on murine colon and breast carcinoma cells in vitro. Additionally, the frequency of T cells with an activated phenotype were increased in non-tumor bearing mice. In the MC38-CEA murine model of colon carcinoma, the addition of Entinostat augmented the antitumor activity promoted by ALT803 plus Ad-CEA resulting in increased survival. Furthermore, in the 4T1 murine model of triple-negative breast cancer, the combination of Entinostat with ALT803 and a monoclonal antibody targeting PD-L1 significantly reduced primary tumor weight relative to ALT803 plus anti-PD-L1 therapy and resulted in a significant reduction of the number of 4T1 tumor-forming cells in the lung. The immune mechanism associated with antitumor efficacy of these multivalent therapies was examined in both the periphery and TME. Overall, these studies provide a rationale for combining Entinostat with multivalent immunotherapy combinations, including cytokines, antibodies targeting PD-L1, and therapeutic cancer vaccines.
Citation Format: Kristin C. Hicks, Karin M. Knudson, Frank R. Jones, Peter Ordentlich, Shahrooz Rabizadeh, Hing C. Wong, James W. Hodge, Jeffrey Schlom, Sofia R. Gameiro. Epigenetic reprogramming of the tumor microenvironment by entinostat increases tumor sensitivity to multivalent immunotherapy combinations with an IL-15 superagonist plus vaccine or immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1740.