Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma.

PURPOSE: Recent advances in immunotherapy highlight the antitumor effects of immune checkpoint inhibition despite a relatively limited subset of patients receiving clinical benefit. The selective class I histone deacetylase inhibitor entinostat has been reported to have immunomodulatory activity including targeting of immune suppressor cells in the tumor microenvironment. Thus, we decided to assess whether entinostat could enhance anti-PD-1 treatment and investigate those alterations in the immunosuppressive tumor microenvironment that contribute to the combined antitumor activity. EXPERIMENTAL DESIGN: We utilized syngeneic mouse models of lung (LLC) and renal cell (RENCA) carcinoma and assessed immune correlates, tumor growth, and survival following treatment with entinostat (5 or 10 mg/kg, p.o.) and a PD-1 inhibitor (10 and 20 mg/kg, s.c.). RESULTS: Entinostat enhanced the antitumor effect of PD-1 inhibition in two syngeneic mouse tumor models by reducing tumor growth and increasing survival. Entinostat inhibited the immunosuppressive function of both polymorphonuclear (PMN)- and monocytic-myeloid derived suppressor cell (M-MDSC) populations. Analysis of MDSC response to entinostat revealed significantly reduced arginase-1, iNOS, and COX-2 levels, suggesting potential mechanisms for the altered function. We also observed significant alterations in cytokine/chemokine release in vivo with a shift toward a tumor-suppressive microenvironment. CONCLUSIONS: Our results demonstrate that entinostat enhances the antitumor effect of PD-1 targeting through functional inhibition of MDSCs and a transition away from an immune-suppressive tumor microenvironment. These data provide a mechanistic rationale for the clinical testing and potential markers of response of this novel combination in solid tumor patients.

Imaging the Progression of Intra-tumor Heterogeneity in Prostate and Ovarian Xenografts Using Dynamic Contrast-Enhanced CT.

The purpose of this study is to measure the progressive intra-tumor heterogeneous physiological states for prostate (CWRrv) and ovarian (SKOV3x) xenograft mouse models. Dynamic contrast-enhanced CT was used to measure the change in a tumor's physiological state when transitioning from stage I (<7 mm diameter) to stage II (7-20 mm diameter). Images from stage I tumors are in the initial stages of angiogenesis: neovasculature growth. A radial heterogeneity begins to form with signs of angiogenic activity throughout the tumor. Stage II tumors develop both a saccular heterogeneity and a strong radial heterogeneity between periphery and core consistent with the effects of inflammatory and maturation processes. Imaging intra-tumor heterogeneity has the potential to track tumor stage and to be used as predictive factor in determining mortality rates.