title: Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility.
abstract: Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is < 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic herpes simplex virus (oHSV), Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy.
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: P-Y
authors.initials: PY
authors.lastname: Wang
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Swain
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Kunkler
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Hutzen
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Arnold
authors.affiliation: Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Streby
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Collins
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Dipasquale
authors.affiliation: Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Stanek
authors.affiliation: Virttu Biologics, Ltd, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Conner
authors.affiliation: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: T H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Glorioso
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Grandi
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Cripe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism*; D053586:Virus Internalization; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011991:Receptors, Virus