The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy

Briere, David; Sudhakar, Niranjan; Woods, David M.; Hallin, Jill; Engstrom, Lars D.; Aranda, Ruth; Chiang, Harrah; Sodré, Andressa L.; Olson, Peter; Weber, Jeffrey S.; Christensen, James G.

doi:10.1007/s00262-017-2091-y

Cited by 116 publications

(113 citation statements)

References 64 publications

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“…This work extends the observations of many investigators using epigenetic strategies to induce elements of the immune response by demonstrating that an antitumor response to an HDAC inhibitor like entinostat in fact may be an immune response. It also confirms studies with another benzamide, mocetinostat, which produced enhanced effects of immunotherapy by drug action on the tumor microenvironment . It adds to the body of knowledge from other investigations with epigenetic agents that have demonstrated the upregulation of virtually all of the components of the immune response, including tumor‐associated antigens, MHC class I and II molecules, transporters associated with antigen processing (TAP1 and TAP2), and costimulatory molecules, such as CD40, CD80, CD86, and intercellular adhesion molecule 1 .…”

Section: Examples Of Recruiting Clinical Trials Using Combinations Ofsupporting

confidence: 73%

Entinostat finds a path: A new study elucidates effects of the histone deacetylase inhibitor on the immune system

Surolia

Bates

2018

Cancer

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Epigenetic therapies have acquired a solid place in clinical armamentariums with the recent approval of enasidenib for isocitrate dehydrogenase 2 (IDH2)-mutated acute myeloid leukemias. This adds to previous approvals of 4 histone deacetylase (HDAC) inhibitors for T-cell lymphomas or multiple myeloma in addition to the long-approved demethylating agents for myeloid disease. But, frustratingly, solid tumor indications have not emerged despite significant efforts, including numerous clinical trials with combination therapies. One recent strategy that has emerged bears perhaps more promise: the use of HDAC inhibitors and DNA-demethylating agents to upregulate components of the immune response and thereby enhance the efficacy of immunotherapy agents, particularly the immune checkpoint blockers. In this issue of Cancer, Smith and colleagues 1 demonstrate the antitumor activity of entinostat in a murine model of ovarian cancer and indicate that efficacy requires adaptive immunity. Such a finding adds support to the ongoing combination studies with immune checkpoint blockade and suggests that this strategy could be applied in ovarian cancer.HDAC inhibitors are epigenetic agents that have been studied intensively for their ability to induce histone hyperacetylation and to upregulate the expression of genes of differentiation and cell cycle control. They do this by inhibiting the HDAC-mediated enzymatic removal of acetyl groups on chromatin, resulting in the aberrant silencing of important tumor suppressors in cancer. Entinostat follows a long history of drug development that began with butyric acid derivatives in the 1980s. Butyrates were the first agents for which histone hyperacetylation was linked with differentiation-eg, with the induction of hemoglobin synthesis in K562 erythroleukemia cells. 2 Searches for other differentiating agents led to identification of the hydroxamic acid vorinostat, and its ability to inhibit HDACs was reported in 1998. 3,4 . Romidepsin was identified for its ability target Ras; but, likewise its ability to inhibit HDACs was reported in 1998. 5-7 Clinical activity and US Food and Drug Administration approval for vorinostat in 2006 and romidepsin in 2009 triggered the development of a spate of HDAC inhibitors, most of them hydroxamic acids like vorinostat. 8 Two other hydroxamic acids gained US Food and Drug Administration approval: belinostat for peripheral T-cell lymphoma and panobinostat in combination with bortezomib and dexamethasone for multiple myeloma. A different drug class was added to the HDAC inhibitors, the benzamides, including entinostat/MS275 and mocetinostat, 9 and, later, chidamide. The first clinical trials of entinostat were reported in solid tumors, leukemias, and lymphomas in 2006 and 2007. 10,11 The enzyme targets for these are the HDAC enzymes, which are divided by structure into 4 classes: enzymes 1, 2, 3, and 8 comprise class I; enzymes 4, 5, 7, and 9 comprise class IIA; enzymes 6 and 10 comprise class IIB; and HDAC11 constitutes class IV. 12 The enzymes are struc...

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Section: Examples Of Recruiting Clinical Trials Using Combinations Ofsupporting

confidence: 73%

Entinostat finds a path: A new study elucidates effects of the histone deacetylase inhibitor on the immune system

Surolia

Bates

2018

Cancer

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“…This durable and stable upregulation is facilitated by the histone acetylation of the PD-L1 and PD-L2 genes and was observed in vitro and in vivo in different solid tumor models [85,86]. Tumor-bearing mice receiving class I HDACi combined with PD-1 blockade exhibited a significant reduction in tumor growth and a better overall survival compared to mice receiving single agents [85][86][87][88] (Table 5). In vivo: Murine renal cell carcinoma (RENCA) luciferase-expressing cells implanted in BALB/c mice.…”

Section: Selective Histone Deacetylase Inhibitorsmentioning

confidence: 87%

“…In vivo: CT26 mouse colon carcinoma cells injected in BALB/c mice. [87] Entinostat + anti PD-1 Lung Kidney…”

Section: Selective Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Immunological Effects of Epigenetic Modifiers

Bezu

Chuang

Liu

et al. 2019

Cancers

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Epigenetic alterations are associated with major pathologies including cancer. Epigenetic dysregulation, such as aberrant histone acetylation, altered DNA methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. Targeting epigenetic cancer hallmarks can be harnessed as an immunotherapeutic strategy, exemplified by the use of pharmacological inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) that can result in the release from the tumor of danger-associated molecular patterns (DAMPs) on one hand and can (re-)activate the expression of tumor-associated antigens on the other hand. This finding suggests that epigenetic modifiers and more specifically the DNA methylation status may change the interaction of chromatin with chaperon proteins including HMGB1, thereby contributing to the antitumor immune response. In this review, we detail how epigenetic modifiers can be used for stimulating therapeutically relevant anticancer immunity when used as stand-alone treatments or in combination with established immunotherapies.Epigenetic alterations compose a natural and fundamental regulatory system of the genetic information contained in the DNA sequence of normal cells. This program is essential for terminal differentiation processes as well as for the maintenance of homeostasis. Epigenetic modifications occur physiologically at several levels and play a regulatory role in various cellular functions such as transcription, RNA splicing, and nuclear export as well as translation. Three mechanisms are considered to induce epigenetic changes, namely DNA methylation, histone modification, and non-coding RNA-associated gene silencing. DNA methylation occurs in healthy cells via the addition of methyl groups by DNA methyltransferases (DNMT1, DNMT2, DNMT3) on position 5 of cytosine residues at CpG-rich promoter regions in order to silence specific genes (in the case of parental genomic imprinting, repeated, or deleterious genes) [5,6]. Post-translational modifications of histones including methylation, acetylation, phosphorylation, and ubiquitination also impact on the accessibility of chromatin and on transcription [7,8] (Figure 1).Cancers 2019, 11, x 2 of 22 occur physiologically at several levels and play a regulatory role in various cellular functions such as transcription, RNA splicing, and nuclear export as well as translation. Three mechanisms are considered to induce epigenetic changes, namely DNA methylation, histone modification, and noncoding RNA-associated gene silencing. DNA methylation occurs in healthy cells via the addition of methyl groups by DNA methyltransferases (DNMT1, DNMT2, DNMT3) on position 5 of cytosine residues at CpG-rich promoter regions in order to silence specific genes (in the case of parental genomic imprinting, repeated, or deleterious genes). [5,6] Post-translational modifications of histones including methylation, acetylation, phosphorylation, and ubiquitination also impact on the a...

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“…Inhibition of HDACs lead to increased histone acetylation, resulting in increased gene expression [75]. Recently, both the HDAC inhibitor mocetinostat and inhibition of HDAC6 independently demonstrated a synergistic effect in combination with ICI, resulting in increased anti-tumor activity in NSCLC and ovarian cancer cell lines by increasing tumor antigen presentation and decreasing immune suppressive cell types [76,77]. Furthermore, in a phase I study, an adenovirus vector encoding the IL-12 gene was injected during surgery in the resection cavity walls of patients with recurrent high-grade glioma, followed by post-operative treatment with the oral activator for human IL-12, veledimex.…”

Section: Discussionmentioning

confidence: 99%

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review

Brahm

Linde

Enting

et al. 2020

Cancers

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The introduction of immune checkpoint inhibitors (ICI), as a novel treatment modality, has transformed the field of oncology with unprecedented successes. However, the efficacy of ICI for patients with glioblastoma or brain metastases (BMs) from any tumor type is under debate. Therefore, we systematically reviewed current literature on the use of ICI in patients with glioblastoma and BMs. Prospective and retrospective studies evaluating the efficacy and survival outcomes of ICI in patients with glioblastoma or BMs, and published between 2006 and November 2019, were considered. A total of 88 studies were identified (n = 8 in glioblastoma and n = 80 in BMs). In glioblastoma, median progression-free (PFS) and overall survival (OS) of all studies were 2.1 and 7.3 months, respectively. In patients with BMs, intracranial responses have been reported in studies with melanoma and non-small-cell lung cancer (NSCLC). The median intracranial and total PFS in these studies were 2.7 and 3.0 months, respectively. The median OS in all studies for patients with brain BMs was 8.0 months. To date, ICI demonstrate limited efficacy in patients with glioblastoma or BMs. Future research should focus on increasing the local and systemic immunological responses in these patients.

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The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy

Cited by 116 publications

References 64 publications

Entinostat finds a path: A new study elucidates effects of the histone deacetylase inhibitor on the immune system

Entinostat finds a path: A new study elucidates effects of the histone deacetylase inhibitor on the immune system

Immunological Effects of Epigenetic Modifiers

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review

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