Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition
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Jennings, Victoria A., Scott, Gina B., Rose, Ailsa M.S., Scott, Karen J., Migneco, Gemma, Keller, Brian, Reilly, Katrina, Donnelly, Oliver, Peach, Howard, Dewar, Donald , Harrington, Kevin J., Pandha, Hardev, Samson, Adel, Vile, Richard G., Melcher, Alan A. and Errington-Mais, Fiona (2019) Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition Molecular Therapy.
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Potentiating Oncolytic.pdf - Version of Record Available under License Creative Commons Attribution. Download (1MB) | Preview |
Official URL: https://doi.org/10.1016/j.ymthe.2019.04.008
Abstract
A clinical oncolytic herpes simplex virus (HSV) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF) alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of anti-melanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs) into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL) priming. Addition of the histone deacetylase inhibitor valproic acid (VPA) to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity.
| Item Type: | Article | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Divisions : | Faculty of Health and Medical Sciences > School of Biosciences and Medicine | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Authors : |
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| Date : | 14 April 2019 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Funders : | National Institute for Health Research (NIHR), Cancer Research UK, Yorkshire Cancer Research, Kay Kendall Leukaemia Fund | |||||||||||||||||||||||||||||||||||||||||||||||||||
| DOI : | 10.1016/j.ymthe.2019.04.008 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Copyright Disclaimer : | © 2019 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncontrolled Keywords : | Oncolytic virus; Herpes simplex virus; HSV, cancer immunotherapy; Histone deacetylase inhibitor; Valproic acid; VPA | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Depositing User : | Clive Harris | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Date Deposited : | 17 May 2019 07:49 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Last Modified : | 17 May 2019 07:49 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| URI: | http://epubs.surrey.ac.uk/id/eprint/851850 |
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