D-104 Harnessing the potential of HDAC inhibitors for immunotherapy combinations

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 evade a tumor targeted immune response by increasing immunosuppressive elements that hamper maturation, recruitment, and function of immune effector cells 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. Studies in our laboratory recently demonstrated that Entinostat, a class I histone deacetylase (HDAC) inhibitor, reverses carcinoma immune escape to human T cell- and NK-mediated lysis and augments the effector function of human NK cells. In preclinical studies, the IL-15/IL-15Rasuperagonist ALT803 has been shown to exhibit tumor control in multiple murine models of cancer through the expansion of NK and CD8+T cells with high effector function. We hypothesized that the antitumor activity promoted by ALT803 in combination with PD-L1 checkpoint blockade or a therapeutic adenoviral vaccine targeting CEA (Ad-CEA) could be augmented by the epigenetic reprograming of the TME induced by Entinostat. The immune mechanisms associated with antitumor efficacy of these multivalent therapies were examined in the TME as well as in the periphery. Results of these studies provide a rationale for combining Entinostat with multivalent immunotherapy combinations, including cytokines, antibodies targeting PD-L1, and therapeutic cancer vaccines.