Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition.
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Date
2019-06-05Author
Jennings, VA
Scott, GB
Rose, AMS
Scott, KJ
Migneco, G
Keller, B
Reilly, K
Donnelly, O
Peach, H
Dewar, D
Harrington, KJ
Pandha, H
Samson, A
Vile, RG
Melcher, AA
Errington-Mais, F
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Dendritic Cells
Killer Cells, Natural
T-Lymphocytes, Cytotoxic
Humans
Simplexvirus
Herpesvirus 1, Human
Melanoma
Skin Neoplasms
Valproic Acid
Granulocyte-Macrophage Colony-Stimulating Factor
Interferon Type I
Biological Products
Antigens, Neoplasm
Drug Therapy, Combination
Cell Survival
Genetic Vectors
Oncolytic Virotherapy
Oncolytic Viruses
Histone Deacetylase Inhibitors
MCF-7 Cells
Antineoplastic Agents, Immunological
Research team
Targeted Therapy
Translational Immunotherapy
Language
eng
Date accepted
2019-04-08
License start date
2019-06
Citation
Molecular therapy : the journal of the American Society of Gene Therapy, 2019, 27 (6), pp. 1139 - 1152
Publisher
CELL PRESS