title: Replication-competent herpes simplex virus retargeted to HER2 as therapy for high-grade glioma.
abstract: Oncolytic herpes simplex viruses (HSVs) represent a novel frontier against tumors resistant to standard therapies, like glioblastoma (GBM). The oncolytic HSVs that entered clinical trials so far showed encouraging results; however, they are marred by the fact that they are highly attenuated. We engineered HSVs that maintain unimpaired lytic efficacy and specifically target cells that express tumor-specific receptors, thus limiting the cytotoxicity only to cancer cells, and leaving unharmed the neighboring tissues. We report on the safety and efficacy in a high-grade glioma (HGG) model of R-LM113, an HSV recombinant retargeted to human epidermal growth factor receptor 2 (HER2), frequently expressed in GBMs. We demonstrated that R-LM113 is safe in vivo as it does not cause encephalitis when intracranially injected in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, extremely sensitive to wild-type HSV. The efficacy of R-LM113 was assessed in a platelet-derived growth factor (PDGF)-induced infiltrative glioma model engineered to express HER2 and transplanted intracranially in adult NOD/SCID mice. Mice injected with HER2-engineered glioma cells infected with R-LM113 showed a doubled survival time compared with mice injected with uninfected cells. A doubling in survival time from the beginning of treatment was obtained also when R-LM113 was administered into already established tumors. These data demonstrate the efficacy of R-LM113 in thwarting tumor growth.
authors.affiliation: Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gambini
authors.forename: Elisa
authors.initials: E
authors.lastname: Reisoli
authors.forename: Irene
authors.initials: I
authors.lastname: Appolloni
authors.forename: Valentina
authors.initials: V
authors.lastname: Gatta
authors.forename: Gabriella
authors.initials: G
authors.lastname: Campadelli-Fiume
authors.forename: Laura
authors.initials: L
authors.lastname: Menotti
authors.forename: Paolo
authors.initials: P
authors.lastname: Malatesta
mesh_terms: D000328:Adult; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D004660:Encephalitis / Q000517:prevention & control; D005818:Genetic Engineering; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060787:Neoplasm Grading; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D018139:Simplexvirus / Q000235:genetics*; D015996:Survival Rate; D014779:Virus Replication
chemical_list: D010982:Platelet-Derived Growth Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human