Abstract P034: Tumor-targeted interleukin-12 and Entinostat combination therapy improves cancer survival by reprogramming the tumor immune cell landscape

Clinical benefit remains elusive for most patients with poorly inflamed carcinomas treated with immune checkpoint blockade. Converting the tumor microenvironment into a functionally inflamed immune hub would increase clinical benefit. By using comprehensive single-cell transcriptome, proteome, and immune cell analysis, we demonstrate here that Entinostat, a class I histone deacetylase inhibitor, facilitates accumulation of the necrosis-targeted recombinant murine immune-cytokine, NHS-rmIL12, in experimental mouse colon carcinomas and poorly immunogenic breast tumor in which the therapy was curative. Combination therapy reprogrammed the tumor innate and adaptive immune milieu to an inflamed landscape, where the concerted action of highly functional CD8+ T cells and activated neutrophils drove a dramatic macrophage M1-like polarization leading to complete tumor eradication in 41.7%-100% of cases. Biomarker signature of favourable overall survival in multiple human tumor types showed close resemblance to the immune pattern generated by Entinostat/NHS-rmIL12 combination therapy. Collectively, these findings provide a rationale for combining NHS-IL12 with Entinostat in the clinical setting. Citation Format: Kristin C. Hicks, Paul L. Chariou, Yohei Ozawa, Christine M. Minnar, Karin M. Knudson, Thomas J. Meyer, Jing Bian, Margaret Cam, Jeffrey Schlom, Sofia R. Gameiro. Tumor-targeted interleukin-12 and Entinostat combination therapy improves cancer survival by reprogramming the tumor immune cell landscape [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P034.