title: A novel approach to cancer therapy using an oncolytic herpes virus to package amplicons containing cytokine genes.
abstract: There are two promising herpes viral-based anticancer strategies: one involves replication-defective viruses to transfer therapeutic transgenes, and the other involves replication-conditional oncolytic viruses, which selectively infect and destroy cancer cells directly. This study examines a novel dual herpesvirus preparation, which combines the immunostimulatory effects of amplicon-mediated IL2 expression with direct viral-induced oncolysis. The oncolytic virus G207 was used as the helper virus to package a herpes simplex virus (HSV)-amplicon vector carrying the gene IL2 (HSV-IL2), yielding a single preparation with two complementary modes of action. In vivo comparison was carried out in a syngeneic squamous cell carcinoma flank tumor model. We directly injected established tumors with HSV-IL2, G207, G207 mixed with HSV-IL2, or G207-packaged HSV-amplicon carrying the IL2 transgene (G207[IL2]). Significant inhibition of tumor growth was seen at 2 weeks in the G207[IL2]-treated tumors relative to controls (0.57+/-0.44 cm(3) versus 39.45+/-5.13 cm(3), P<0.00001), HSV-IL2 (20.97+/-4.60 cm(3)), and the G207 group (7.71+/-2.10 cm(3)). This unique use of a replication-conditional, oncolytic virus to package a replication-incompetent amplicon vector demonstrates impressive efficacy in vitro and in vivo, and avoids the theoretical concerns of recombination with reversion to wild type.
authors.affiliation: Department of Otorhinolaryngology, New York Presbyterian Medical Center-Cornell University Medical Center, New York, NY 10021, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Carew
authors.forename: D A
authors.initials: DA
authors.lastname: Kooby
authors.forename: M W
authors.initials: MW
authors.lastname: Halterman
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: H J
authors.initials: HJ
authors.lastname: Federoff
authors.forename: Y
authors.initials: Y
authors.lastname: Fong
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016923:Cell Death; D002455:Cell Division; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D007376:Interleukin-2