title: Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models.
abstract: Oncolytic herpes simplex virus (oHSV) can potentially spread throughout the tumor, reach isolated infiltrating cells, kill them, and deliver anticancer agents. However, the host responds to oHSV by inducing intratumoral infiltration of macrophages that can engulf the virus, limiting the potential of this therapeutic strategy. Hypervascularity is a pathognomonic feature of glioblastoma (GBM) and is a promising therapeutic target. Antiangiogenic treatments have multiple benefits, including the capacity to increase oHSV efficacy by suppressing macrophage extravasation and infiltration into the tumor. Angiostatin is an antiangiogenic polypeptide, and interleukin-12 (IL-12) is an immunostimulatory cytokine with strong antiangiogenic effects. Clinical use of each has been limited by delivery issues and systemic toxicity. We tested a combination treatment strategy using oHSVs expressing angiostatin (G47Δ-mAngio) and IL-12 (G47Δ-mIL12) in two orthotopic human GBM models. Intratumoral injection of G47Δ-mAngio and G47Δ-mIL12 in mice bearing intracranial U87 or tumors derived from glioblastoma stem cells significantly prolonged survival compared to each armed oHSV alone. This was associated with increased antiangiogenesis and virus spread and decreased macrophages. These data support the paradigm of using oHSV expressing different antiangiogenic agents and show for the first time that oHSVs expressing angiostatin and IL-12 can improve efficacy in human GBM models.
authors.affiliation: Brain Tumor Research Center, Molecular Neurosurgery Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Giulia
authors.initials: G
authors.lastname: Fulci
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Tooba A
authors.initials: TA
authors.lastname: Cheema
authors.forename: Jason S
authors.initials: JS
authors.lastname: Buhrman
authors.forename: Deva S
authors.initials: DS
authors.lastname: Jeyaretna
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer Rachamimov
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D050504:Oncolytic Viruses / Q000235:genetics*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D018664:Interleukin-12; D043168:Angiostatins