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Translational Cancer Mechanisms and Therapy

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 and Sofia R. Gameiro
Kristin C. Hicks
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Karin M. Knudson
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Karin L. Lee
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Duane H. Hamilton
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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James W. Hodge
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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  • ORCID record for James W. Hodge
William D. Figg
2Clinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Peter Ordentlich
3Syndax Pharmaceuticals, Inc., Waltham, Massachusetts.
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Frank R. Jones
4ImmunityBio, Culver City, California.
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Shahrooz Rabizadeh
4ImmunityBio, Culver City, California.
5NantOmics, LLC, Culver City, California.
6NantWorks, Culver City, California.
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Patrick Soon-Shiong
4ImmunityBio, Culver City, California.
5NantOmics, LLC, Culver City, California.
6NantWorks, Culver City, California.
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Jeffrey Schlom
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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  • ORCID record for Jeffrey Schlom
  • For correspondence: schlomj@mail.nih.gov
Sofia R. Gameiro
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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DOI: 10.1158/1078-0432.CCR-19-0727 Published February 2020
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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.

This article is featured in Highlights of This Issue, p. 521

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:704–16

  • Received March 1, 2019.
  • Revision received July 9, 2019.
  • Accepted October 18, 2019.
  • Published first October 23, 2019.
  • ©2019 American Association for Cancer Research.
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Clinical Cancer Research: 26 (3)
February 2020
Volume 26, Issue 3
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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 and Sofia R. Gameiro
Clin Cancer Res February 1 2020 (26) (3) 704-716; DOI: 10.1158/1078-0432.CCR-19-0727

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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 and Sofia R. Gameiro
Clin Cancer Res February 1 2020 (26) (3) 704-716; DOI: 10.1158/1078-0432.CCR-19-0727
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