title: Imaging a Genetically Engineered Oncolytic Vaccinia Virus (GLV-1h99) Using a Human Norepinephrine Transporter Reporter Gene.
abstract: OBJECTIVE
  Oncolytic viral therapy continues to be investigated for the treatment of cancer, and future studies in patients would benefit greatly from a noninvasive modality for assessing virus dissemination, targeting, and persistence. The purpose of this study was to determine if a genetically modified vaccinia virus, GLV-1h99, containing a human norepinephrine transporter (hNET) reporter gene, could be sequentially monitored by [(123)I]metaiodobenzylguanidine (MIBG) gamma-camera and [(124)I]MIBG positron emission tomography (PET) imaging.
  
  
  METHODS
  GLV-1h99 was tested in human malignant mesothelioma and pancreatic cancer cell lines for cytotoxicity, expression of the hNET protein using immunoblot analysis, and [(123)I]MIBG uptake in cell culture assays. In vivo [(123)I]MIBG gamma-camera and serial [(124)I]MIBG PET imaging was done in MSTO-211H orthotopic pleural mesothelioma tumors.
  
  
  RESULTS
  GLV-1h99 successfully infected and provided dose-dependent levels of transgene hNET expression in human malignant mesothelioma and pancreatic cancer cells. The time course of [(123)I]MIBG accumulation showed a peak of radiotracer uptake at 48 hours after virus infection in vitro. In vivo hNET expression in MSTO-211H pleural tumors could be imaged by [(123)I]MIBG scintigraphy and [(124)I]MIBG PET 48 and 72 hours after GLV-1h99 virus administration. Histologic analysis confirmed the presence of GLV-1h99 in tumors.
  
  
  CONCLUSIONS
  GLV-1h99 shows high mesothelioma tumor cell infectivity and cytotoxic efficacy. The feasibility of imaging virus-targeted tumor using the hNET reporter system with [(123)I]MIBG gamma-camera and [(124)I]MIBG PET was shown in an orthotopic pleural mesothelioma tumor model. The inclusion of human reporter genes into recombinant oncolytic viruses enhances the potential for translation to clinical monitoring of oncolytic viral therapy.
authors.affiliation: Departments of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Brader
authors.forename: Kaitlyn J
authors.initials: KJ
authors.lastname: Kelly
authors.forename: Nanhai
authors.initials: N
authors.lastname: Chen
authors.forename: Yong A
authors.initials: YA
authors.lastname: Yu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Pat
authors.initials: P
authors.lastname: Zanzonico
authors.forename: Eva M
authors.initials: EM
authors.lastname: Burnazi
authors.forename: Rashid E
authors.initials: RE
authors.lastname: Ghani
authors.forename: Inna
authors.initials: I
authors.lastname: Serganova
authors.forename: Hedvig
authors.initials: H
authors.lastname: Hricak
authors.forename: Aladar A
authors.initials: AA
authors.lastname: Szalay
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Blasberg
mesh_terms: D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D015902:Gamma Cameras; D005818:Genetic Engineering; D006801:Humans; D015151:Immunoblotting; D007457:Iodine Radioisotopes; D008297:Male; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D049268:Positron-Emission Tomography; D014183:Transplantation, Heterologous; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D007457:Iodine Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019797:3-Iodobenzylguanidine