An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine

Lai, M-D; Cs, Chen; Cr, Yang; Yuan, S-Y; Tsai, J. T.; Cf, Tu; Cc, Wang; Yen, Meng‐Chi; Lin, Chi-Chen

doi:10.1038/cgt.2009.65

Cited by 29 publications

(27 citation statements)

References 36 publications

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“…HDACi-mediated enhancement of transgene expression from the CMV promoter would be beneficial not only for viral gene therapy but also for nonviral approaches. For example, recent studies demonstrated that HDACi enhanced the efficacy of a CMV-driven DNA vaccine and may also improve polymer-mediated gene delivery [16, 17]. Interestingly, HDACi inhibited gene expression from a prostate-specific promoter, indicating that combination of these drugs with tissue-specific promoters needs to be carefully evaluated [18].…”

Section: Resultsmentioning

confidence: 99%

Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells

2012

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Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer.

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Section: Resultsmentioning

confidence: 99%

Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells

2012

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“…Together, these findings strongly suggest that the successful elimination of HIV-1-infected cells during latency-reversing treatment depends on host immune responses that kill cells in which viral gene expression is reactivated. Interestingly, experience from preclinical and clinical studies with HDACi in the context of oncologic diseases similarly indicates that elimination of malignant cells during HDACi therapy critically depends on effective host immune activity (35) and that combinations of HDACi and immune-based interventions may lead to more potent therapeutic effects against cancer cells (45)(46)(47). In the present work, we conducted a detailed and comprehensive analysis of innate and adaptive host immune responses during treatment with the HDACi panobinostat in ART-treated HIV-1-infected patients.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Olesen

Viganó

Rasmussen

et al. 2015

J Virol

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The pharmaceutical reactivation of dormant HIV-1 proviruses by histone deacetylase inhibitors (HDACi) represents a possible strategy to reduce the reservoir of HIV-1-infected cells in individuals treated with suppressive combination antiretroviral therapy (cART). However, the effects of such latency-reversing agents on the viral reservoir size are likely to be influenced by host immune responses. Here, we analyzed the immune factors associated with changes in proviral HIV-1 DNA levels during treatment with the potent HDACi panobinostat in a human clinical trial involving 15 cART-treated HIV-1-infected patients. We observed that the magnitude, breadth, and cytokine secretion profile of HIV-1-specific CD8 T cell responses were unrelated to changes in HIV-1 DNA levels in CD4 T cells during panobinostat treatment. In contrast, the proportions of CD3 ؊ CD56 ؉ total NK cells and CD16 ؉ CD56 dim NK cells were inversely correlated with HIV-1 DNA levels throughout the study, and changes in HIV-1 DNA levels during panobinostat treatment were negatively associated with the corresponding changes in CD69 ؉ NK cells. Decreasing levels of HIV-1 DNA during latency-reversing treatment were also related to the proportions of plasmacytoid dendritic cells, to distinct expression patterns of interferon-stimulated genes, and to the expression of the IL28B CC genotype. Together, these data suggest that innate immune activity can critically modulate the effects of latency-reversing agents on the viral reservoir and may represent a target for future immunotherapeutic interventions in HIV-1 eradication studies. IMPORTANCECurrently available antiretroviral drugs are highly effective in suppressing HIV-1 replication, but the virus persists, despite treatment, in a latent form that does not actively express HIV-1 gene products. One approach to eliminate these cells, colloquially termed the "shock-and-kill" strategy, focuses on the use of latency-reversing agents that induce active viral gene expression in latently infected cells, followed by immune-mediated killing. Panobinostat, a histone deacetylase inhibitor, demonstrated potent activities in reversing HIV-1 latency in a recent pilot clinical trial and reduced HIV-1 DNA levels in a subset of patients. Interestingly, we found that innate immune factors, such as natural killer cells, plasmacytoid dendritic cells, and the expression patterns of interferon-stimulated genes, were most closely linked to a decline in the HIV-1 DNA level during treatment with panobinostat. These data suggest that innate immune activity may play an important role in reducing the residual reservoir of HIV-1-infected cells.A lthough for a long time regarded as an elusive goal, the development of clinical interventions that lead to a long-term, drug-free remission of HIV-1 infection is increasingly being recognized as a more and more realistic objective (1-4). This is in part related to the identification of patients with a sterilizing or functional cure of HIV-1 infection, who provide living evidence that, ...

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“…Since transcriptional silencing is associated with HDAC-mediated chromatin condensation, HDAC inhibitors have been reported to influence virus promoter-driven gene expression following DNA vaccination. AR-42 (also known as OSU-HDAC42; ApexBio), a hydroxamate-tethered phenylbutyrate derivative that acts as a pan-HDAC inhibitor, increased the expression of Her-2/neu DNA vaccine and resulted in a greater infiltration of lymphocytes into tumors in mice [68]. HDAC inhibition enhanced antitumor response induced by Her-2/neu DNA vaccine, leading to significant delays in tumor progression and extending the lifespan of these mice.…”

Section: Hdac Inhibitors and Cancer Vaccinesmentioning

confidence: 99%

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

2015

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Understanding the contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides the rationale for the use of epigenetic modulators, such as histone deacetylase (HDAC) inhibitors, in cancer therapy. HDAC inhibitors have been approved as single agents for cutaneous and peripheral T-cell lymphoma and have shown promising activity in reversing therapy resistance in other tumor types. The effects of HDAC inhibitors on immune modulation have created a recent interest in their potential role in immunotherapy. This review describes the current understanding on integrating HDAC inhibitors into various immunotherapeutic approaches, such as cancer vaccines, adoptive T-cell transfer and immune checkpoint inhibitors. Furthermore, it summarizes promising treatment strategies in epigenetic immune priming from clinical trials that are currently underway.

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An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine

Cited by 29 publications

References 36 publications

Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells

Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

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