Mechanisms of immunomodulation with epigenetic therapy

Project Summary/Abstract
Immune checkpoint inhibitors (ICI) targeting programmed cell death protein 1 (PD-1) or its ligand have produced
unprecedented clinical benefit for some cancers but have failed in others including pancreatic adenocarcinoma
(PDA). PDAs display low T cell infiltration and high numbers of immunosuppressive cell types including myeloid-
derived suppressor cells (MDSCs). Combination approaches that reverse the intrinsic immunosuppressive
biology of PDA will be key to converting PDA into an ICI-sensitive tumor type. Our group and others reported
that epigenetic therapies can influence both tumors and other cells in the tumor microenvironment (TME),
including immune and stromal cells. We reported that the histone deacetylase inhibitor (HDACi) entinostat
modulates myeloid-derived suppressor cells (MDSCs), resulting in a less immunosuppressive population. We
have translated these preclinical findings into an ongoing clinical trial of entinostat in combination with the PD-1
inhibitor nivolumab, on which we have observed multiple clinical responses in metastatic PDA patients. The
current proposal builds upon our existing pre-clinical data to answer important mechanistic questions as to how
epigenetic modulatory therapies reprogram the TME for systemic immunotherapy. We hypothesize that HDACi
therapy can modulate multiple inflammatory, stromal and tumor cells in the PDA TME, converting PDA tumors
from immune excluding into immune responsive cancers. We will first evaluate HDACi modified pathways from
our preclinical findings to further identify specific pathways that are altered by HDACi. This work will specifically
test the hypothesis generated from our preliminary data that STAT3 modulation mediates entinostat’s effects on
MDSC function through regulation of multiple inflammatory pathways, resulting in the antitumor effect seen when
given in combination with anti-PD1 therapy. We will also expand our investigation of the immunomodulatory
effects of HDACi to evaluate the effect of entinostat on focused immune populations that receive signals from
MDSCs. We will use our preclinical models to test the hypothesis that entinostat uncovers mutation-associated
pancreatic cancer neoantigens that can augment antitumor immunity alone or in combination with systemic
immunotherapies. We will confirm our preclinical findings using our unique biospecimens collected from our
ongoing clinical trial of entinostat in combination with anti-PD1 therapy in PDA that is banking serial biopsies at
baseline, after entinostat monotherapy and after combination therapy, allowing assessment of the immune
impact of HDACi alone and in combination with ICI on the TME. In addition, we hope to build upon our clinical
experience with entinostat plus nivolumab by studying rational combinations of additional novel agents, providing
a preclinical basis for future therapeutic trials.

Grant Number: 5P01CA247886-05
NIH Institute/Center: NIH
Principal Investigator: Nilofer Azad