The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat

Tomita, Yusuke; Lee, Min Jung; Tomita, Shunsuke; Chumsri, Saranya; Cruickshank, Scott; Ordentlich, Peter; Trepel, Jane B.

doi:10.1080/2162402x.2016.1219008

Cited by 61 publications

(49 citation statements)

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“…Recent reports suggest that HDAC inhibition alters the cytokine release and may change the function of innate immune cell infiltrates in the tumor microenvironment (6,8,12,35). Interestingly, correlative studies performed in breast cancer patients receiving entinostat showed a decrease in both monocytic and granulocytic MDSCs (35).…”

Section: Discussionmentioning

confidence: 99%

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Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Orillion

Hashimoto

Damayanti

et al. 2017

Clinical Cancer Research

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308

232

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Purpose Recent advances in immunotherapy highlight the antitumor effects of immune- checkpoint inhibition despite a relatively limited subset of patients receiving clinical benefit. The selective class I histone deacetylase inhibitor (HDACi) entinostat has been reported to have immunomodulatory activity including targeting of immune suppressor cells in the tumor microenvironment. Thus, we decided to assess whether entinostat could enhance anti-PD-1 treatment and investigate those alterations in the immunosuppressive tumor microenvironment that contribute to the combined anti-tumor activity. Experimental design We utilized syngeneic mouse models of lung (LLC) and renal cell (RENCA) carcinoma, and assessed immune correlates, tumor growth and survival following treatment with entinostat (5 or 10 mg/kg, P.O.) and a PD-1 inhibitor (10 and 20 mg/kg, s.c.). Results Entinostat enhanced the antitumor effect of PD-1 inhibition in two syngeneic mouse tumor models by reducing tumor growth and increasing survival. Entinostat inhibited the immunosuppressive function of both PMN- and M-MDSC populations. Analysis of MDSC response to entinostat revealed significantly reduced arginase-1, iNOS and COX-2 levels, suggesting potential mechanisms for the altered function. We also observed significant alterations in cytokine/chemokine release in vivo with a shift from an immunosuppressive to a tumor suppressive microenvironment. Conclusions Our results demonstrate that entinostat enhances the antitumor effect of PD-1 targeting through functional inhibition of MDSCs, and a transition away from an immune suppressive tumor microenvironment. These data provide a mechanistic rationale for the clinical testing and potential markers of response of this novel combination in solid tumor patients.

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, correlative studies performed in breast cancer patients receiving entinostat showed a decrease in both monocytic and granulocytic MDSCs (35). In our experimental conditions, we actually observed an increase in both monocytic and granulocytic subsets of the MDSC population.…”

Section: Discussionmentioning

confidence: 99%

Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Orillion

Hashimoto

Damayanti

et al. 2017

Clinical Cancer Research

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308

232

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“…Entinostat, like domatinostat a class Iselective HDACi, was shown to reduce the number and function of MDSCs in murine models in which combination therapies with checkpoint inhibitors were evaluated [48]. Based on this mode of action, peripheral MDSCs were evaluated in advanced breast cancer patients treated with a combination of entinostat and exemestane [21]. Blood samples collected after two weeks of therapy revealed significantly decreased MDSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Although epigenetic drugs are being evaluated in combination with immunotherapy in several clinical trials, translational data on the immunomodulatory effects of class I-selective HDACis are scarce. In breast cancer patients, the number of peripheral MDSCs was significantly reduced upon treatment with the HDACi entinostat and the aromatase inhibitor exemestane [21].…”

Section: Introductionmentioning

confidence: 99%

Domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment (TIME)

Bretz¹,

Parnitzke²,

Kronthaler³

et al. 2019

j. immunotherapy cancer

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Background: The efficacy of PD-(L)1 blockade depends on the composition of the tumor immune microenvironment (TIME) and is generally higher in tumors with pre-existing cytotoxic T cells (CTL) than in those with low CTL numbers. Nonetheless, a significant proportion of patients with pre-existing immunity fail to respond, indicating a therapeutic potential for combining PD-(L)1 blockade with additional immunomodulatory agents in both CTL-high and-low immune phenotypes. Here, we evaluated domatinostat (4SC-202), a class I-selective histone deacetylase (HDAC) inhibitor, for its effect on the TIME and its antitumoral efficacy using syngeneic mouse models with CTL-high or CTL-low tumors. Methods: Domatinostat was evaluated in PD-1 blockade-insensitive CTL-low (CT26) and CTL-high (C38) syngeneic models alone and in combination with different immune-inhibitory and-stimulatory approaches. Effects on the immunophenotype were assessed via flow cytometry and RNA-seq analyses. The changes in RNA-seq-based immune signatures determined in a murine setting were investigated in patient samples from the first-dose cohort of the SENSITIZE trial (NCT03278665) evaluating domatinostat combined with pembrolizumab in advanced-stage melanoma patients refractory/nonresponding to PD-1 blockade. Results: Domatinostat increased the expression of antigen-presenting machinery (APM) genes and MHC class I and II molecules, along with CTL infiltration, in tumors of both immune phenotypes. In combination with PD-(L)1 blockade, domatinostat augmented antitumor effects substantially above the effects of single-agent therapies, displaying greater benefit in tumors with pre-existing CTLs. In this setting, the combination of domatinostat with agonistic anti-4-1BB or both PD-1 and LAG3 blockade further increased the antitumor efficacy. In CTL-low tumors, domatinostat enhanced the expression of genes known to reinforce immune responses against tumors. Specifically, domatinostat increased the expression of Ifng and genes associated with responses to pembrolizumab and nivolumab. Clinically, these findings were confirmed in patients with advanced melanoma treated with domatinostat for 14 days, who demonstrated elevated expression of APM and MHC genes, the IFNG gene, and the IFN-γ and pembrolizumab response signatures in individual tumor samples. Conclusion: In summary, these data suggest a promising potential of domatinostat in combination with immunotherapy to improve the outcome of refractory cancer patients.

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“…Interestingly, HDAC inhibition has been shown to increase PD-L1 expression in preclinical models, including in combination with a demethylating agent 29, 30 . Furthermore, there is both preclinical and clinical evidence that entinostat may affect myeloid suppressive derived cells 31, 32 . Thus, over the next years, several clinical trials will test novel combinations of immunotherapies for ccRCC including checkpoint inhibitors, vaccines, adoptive T-cell therapy and T-cell agonists 33 , and HDAC inhibitors may provide an additional tool to modulate the immune response more effectively.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870)

Пили

Quinn

Hammers

et al. 2017

Clinical Cancer Research

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Purpose Based on preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high dose interleukin 2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic clear cell renal cell carcinoma (ccRCC). Experimental Design Clear cell histology, no prior treatments, and being sufficiently fit to receive high dose IL-2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed standard dose of IL-2 (600,000 units/kg IV). Each cycle was 85 days. The primary end point was objective response rate and toxicity. Secondary end points included progression-free survival and overall survival. Results 47 patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% (95% CI 22%–53%), the median progression-free survival was 13.8 months (95% CI 6.0–18.8), and the median overall survival was 65.3 months (95% CI 52.6.–65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Treg were observed following treatment with entinostat, and lower numbers were associated with response (p=0.03). Conclusions This trial suggests a promising clinical activity for entinostat in combination with high dose Il-2 in ccRCC patients, and provides the first example of an epigenetic agent being rationally combined with immunotherapy.

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The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat

Cited by 61 publications

References 50 publications

Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment (TIME)

Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870)

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