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: Eleonora Gambini, Elisa Reisoli, Irene Appolloni, Valentina Gatta, Gabriella Campadelli-Fiume, Laura Menotti, Paolo Malatesta
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 20 Issue 5 Pg. 994-1001 (May 2012) ISSN: 1525-0024 [Electronic] United States
• PMID: 22354378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Platelet-Derived Growth Factor
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adult
• Animals
• Brain Neoplasms (genetics, mortality, therapy)
• Encephalitis (prevention & control)
• Genetic Engineering
• Genetic Vectors
• Glioma (genetics, mortality, therapy)
• Humans
• Injections, Intraventricular
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Grading
• Neoplasm Transplantation
• Oncolytic Virotherapy (methods)
• Platelet-Derived Growth Factor (genetics)
• Receptor, ErbB-2 (genetics)
• Simplexvirus (genetics)
• Survival Rate
• Virus Replication