title: Preferential replication of systemically delivered oncolytic vaccinia virus in focally irradiated glioma xenografts.
abstract: OBJECTIVE
  Radiotherapy is part of the standard of care in high-grade gliomas but its outcomes remain poor. Integrating oncolytic viruses with standard anticancer therapies is an area of active investigation. The aim of this study was to determine how tumor-targeted ionizing radiation (IR) could be combined with systemically delivered oncolytic vaccinia virus.
  
  
  METHODS
  U-87 glioma xenografts were grown subcutaneously or orthotopically. Oncolytic vaccinia viruses GLV-1h68 and LIVP 1.1.1 were injected systemically and IR was given focally to glioma xenografts. In a bilateral tumor model, glioma xenografts were grown in both flanks, oncolytic vaccinia was injected systemically and radiation was delivered specifically to the right flank tumor, whereas the left flank tumor was shielded. Viral replication and tumor regression, after systemic injection, was analyzed and compared in irradiated and nonirradiated glioma xenografts.
  
  
  RESULTS
  Systemically administered oncolytic vaccinia virus replicated to higher titers in preirradiated U-87 xenografts than in nonirradiated glioma xenografts. This increased oncolytic viral replication correlated with increased tumor xenograft regression and mouse survival in subcutaneous and orthotopic U-87 glioma models compared with monotherapies. The ability of focal IR to mediate selective replication of oncolytic vaccinia was shown in a bilateral glioma model in which systemically administered oncolytic vaccinia replicated preferentially in the irradiated tumor compared with the nonirradiated tumor in the same mouse.
  
  
  CONCLUSIONS
  These findings show a potential clinical role of focal IR in sensitizing irradiated tumor sites for preferential vaccinia virus-mediated oncolysis.
authors.affiliation: Department of Radiation Medicine and Applied Sciences and Center for Advanced Radiotherapy Technologies, University of California San Diego, La Jolla, California 92093, USA. sjadvani@ucsd.edu
authors.forename: Sunil J
authors.initials: SJ
authors.lastname: Advani
authors.forename: Lisa
authors.initials: L
authors.lastname: Buckel
authors.forename: Nanhai G
authors.initials: NG
authors.lastname: Chen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Scanderbeg
authors.forename: Ulrike
authors.initials: U
authors.lastname: Geissinger
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yong A
authors.initials: YA
authors.lastname: Yu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Aguilar
authors.forename: Arno J
authors.initials: AJ
authors.lastname: Mundt
authors.forename: Aladar A
authors.initials: AA
authors.lastname: Szalay
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D011839:Radiation, Ionizing; D015996:Survival Rate; D014615:Vaccinia / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D014616:Vaccinia virus / Q000235:genetics; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays