Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2019-06-05
Date Accepted
2019-04-08
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.
Citation
Molecular therapy : the journal of the American Society of Gene Therapy, 2019, 27 (6), pp. 1139 - 1152
Source Title
Publisher
CELL PRESS
ISSN
1525-0016
eISSN
1525-0024
Research Team
Targeted Therapy
Translational Immunotherapy
Translational Immunotherapy