Cooperative Immune-Mediated Mechanisms of the HDAC Inhibitor Entinostat, an IL15 Superagonist, and a Cancer Vaccine Effectively Synergize as a Novel Cancer Therapy.

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 CD8+ T-cell activation and cytokine production, there was no reduction in tumor burden and poor tumor infiltration of CD8+ 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 CD8+ T cells with maximal granzyme B, T-cell responses to multiple tumor-associated antigens, increased serum IFNγ, 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 3 Pg. 704-716 (02 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 31645354 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Benzamides
• Cancer Vaccines
• Histone Deacetylase Inhibitors
• Interleukin-15
• Pyridines
• entinostat

Topics

• Animals
• Apoptosis
• Benzamides (pharmacology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cancer Vaccines
• Cell Proliferation
• Colonic Neoplasms (drug therapy, immunology, metabolism, pathology)
• Drug Synergism
• Drug Therapy, Combination
• Female
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Immunotherapy
• Interleukin-15 (agonists)
• Lymphocyte Activation (drug effects, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Pyridines (pharmacology)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Triple Negative Breast Neoplasms (drug therapy, immunology, metabolism, pathology)
• Tumor Burden
• Tumor Cells, Cultured
• Tumor Microenvironment