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An Oncolytic HSV-1 Mutant Expressing ICP34.5 under Control of a Nestin Promoter Increases Survival of Animals even when Symptomatic from a Brain Tumor

¹ Dardinger Center for Neuro-oncology, Department of Neurological Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; ² Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; and ³ Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

Requests for reprints: E. Antonio Chiocca or Yoshinaga Saeki, Dardinger Center for Neuro-oncology, Department of Neurological Surgery, The Ohio State University Medical Center Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, N-1017 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-9312; Fax: 614-293-4281; E-mail: Chiocca-1{at}medctr.osu.edu or saeki-1{at}medctr.osu.edu.

Oncolytic herpes simplex virus-1 (HSV-1) mutants possessing mutations in the ICP34.5 and ICP6 genes have proven safe through clinical trials. However, ICP34.5-null viruses may grow poorly in cells due to their inability to prevent host-cell shut-off of protein synthesis caused by hyperphosphorylation of eukaryotic initiation factor 2. To increase tumor selectivity, glioma-selective expression of ICP34.5 in the context of oncolysis may be useful. Malignant gliomas remain an incurable disease. One molecular marker of malignant gliomas is expression of the intermediate filament nestin. Expression of nestin mRNA was confirmed in 6 of 6 human glioma lines and in 3 of 4 primary glioma cells. Normal human astrocytes were negative. A novel glioma-selective HSV-1 mutant (rQNestin34.5) was thus engineered by expressing ICP34.5 under control of a synthetic nestin promoter. Replication, cellular propagation, and cytotoxicity of rQNestin34.5 were significantly enhanced in cultured and primary human glioma cell lines compared with control virus. However, replication, cellular propagation, and cytotoxicity of rQNestin34.5 in normal human astrocytes remained quantitatively similar to that of control virus. In glioma cell lines infected with rQNestin34.5, the level of phospho-eukaryotic initiation factor 2 was lower than that of cells infected by control rHsvQ1, confirming selective ICP34.5 expression in glioma cells. In vivo, rQNestin34.5 showed significantly more potent inhibition of tumor growth compared with control virus. Treatment in the brain tumor model was instituted on animal's display of neurologic symptoms, which usually led to rapid demise. rQNestin34.5 treatment doubled the life span of these animals. These results show that rQNestin34.5 could be a potent agent for the treatment of malignant glioma.

Key Words: Viral therapy • oncolytic viruses • glioma • gene therapy • experimental therapy

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