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Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition

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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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
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
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.
Samson, Adel
Vile, Richard G.
Melcher, Alan A.
Errington-Mais, Fiona
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 (
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

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