Journal
CLINICAL CANCER RESEARCH
Volume 26, Issue 3, Pages 704-716Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-0727
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Funding
- Intramural Research Program of the Center for Cancer Research, NCI, NIH
- NCI
- Syndax Pharmaceuticals, Inc.
- NantBioScience, Inc.
- NATIONAL CANCER INSTITUTE [ZIABC010661, ZIABC010944, ZICSC006537, ZICSC006536] Funding Source: NIH RePORTER
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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 IFN gamma, reduction of regulatory (TM) 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.
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