Cooperative immune-mediated mechanisms of the HDAC inhibitor entinostat, an IL15 superagonist, and a cancer vaccine effectively synergize as a novel cancer therapy

Kristin C. Hicks, Karin M. Knudson, Karin L. Lee, Duane H. Hamilton, James W. Hodge, William D. Figg, Peter Ordentlich, Frank R. Jones, Shahrooz Rabizadeh, Patrick Soon-Shiong, Jeffrey Schlom*, Sofia R. Gameiro

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Purpose: Immunotherapy has demonstrated clinical efficacy in subsets of patients with solid carcinomas. Multimodal therapies using agents that can affect different arms of the immune system and/or tumor microenvironment (TME) might increase clinical responses. Experimental Design: We demonstrate that entinostat, a class I histone deacetylase inhibitor, enhances the antitumor efficacy of the IL15 superagonist N-803 plus vaccine in 4T1 triple-negative breast and MC38-CEA colon murine carcinoma models. A comprehensive immune and gene-expression analysis was performed in the periphery and/or TME of MC38-CEA tumor–bearing mice. Results: Although N-803 plus vaccine induced peripheral CD8þ T-cell activation and cytokine production, there was no reduction in tumor burden and poor tumor infiltration of CD8þ T cells with minimal levels of granzyme B. For the first time, we demonstrate that the addition of entinostat to N-803 plus vaccine promoted significant tumor control, correlating with increased expression of genes associated with tumor inflammation, enhanced infiltration of activated CD8þ T cells with maximal granzyme B, T-cell responses to multiple tumor-associated antigens, increased serum IFNg, reduction of regulatory T cells in the TME, and decreased expression of the checkpoint V-domain Ig suppressor of T-cell activation (VISTA) on multiple immune subsets. Conclusions: Collectively, these data demonstrate that the synergistic combination of entinostat, N-803, and vaccine elicits potent antitumor activity by generating a more inflamed TME. These findings thus form the rationale for the use of this combination of agents for patients harboring poorly or noninflamed solid carcinomas.

Original languageEnglish
Pages (from-to)704-716
Number of pages13
JournalClinical Cancer Research
Volume26
Issue number3
DOIs
StatePublished - 1 Feb 2020
Externally publishedYes

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