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.
Original language | English (US) |
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Pages (from-to) | 1139-1152 |
Number of pages | 14 |
Journal | Molecular Therapy |
Volume | 27 |
Issue number | 6 |
DOIs | |
State | Published - Jun 5 2019 |
Keywords
- HSV,cancer immunotherapy
- VPA
- herpes simplex virus
- histone deacetylase inhibitor
- oncolytic virus
- valproic acid
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery