title: Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of neuroblastoma.
abstract: Despite intensive research efforts and therapeutic advances over the last few decades, the pediatric neural crest tumor, neuroblastoma, continues to be responsible for over 15% of pediatric cancer deaths. Novel therapeutic options are needed for this tumor. Recently, investigators have shown that mice with syngeneic murine gliomas treated with an engineered, neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ 1 34.5 gene, enabling replication in tumor cells but precluding infection of normal neural cells. We hypothesized that M002 would also be effective in the neural crest tumor, neuroblastoma. We showed that M002 infected, replicated, and decreased survival in neuroblastoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly decreased tumor growth, and that this effect was augmented with the addition of ionizing radiation. Importantly, survival could be increased by subsequent doses of radiation without re-dosing of the virus. Finally, these studies showed that the primary entry protein for oHSV, CD111 was expressed by numerous neuroblastoma cell lines and was also present in human neuroblastoma specimens. We concluded that M002 effectively targeted neuroblastoma and that this oHSV may have potential for use in children with unresponsive or relapsed neuroblastoma.
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Gillory
authors.forename: Michael L
authors.initials: ML
authors.lastname: Megison
authors.forename: Jerry E
authors.initials: JE
authors.lastname: Stewart
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mroczek-Musulman
authors.forename: Hugh C
authors.initials: HC
authors.lastname: Nabers
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Waters
authors.forename: Virginia
authors.initials: V
authors.lastname: Kelly
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Coleman
authors.forename: James M
authors.initials: JM
authors.lastname: Markert
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Friedman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Beierle
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D018845:CD11 Antigens / Q000032:analysis; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics* / Q000502:physiology; D014709:Vero Cells; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018845:CD11 Antigens; D050794:STAT1 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases