title: Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity.
abstract: Among the best-characterized genetic alterations in gliomas is the amplification of the epidermal growth factor receptor (EGFR) gene, present in approximately 40% of glioblastoma multiforme, and frequently associated with the EGFRvIII gene rearrangement. We have previously shown that attenuated vaccine strains of measles virus have potent antitumor activity against gliomas, and identified H protein mutations, which ablate recognition of the natural measles virus receptors CD46 and SLAM. Retargeted recombinant viruses were generated from the measles Edmonston-NSe vaccine strain displaying a single-chain antibody against EGFRvIII at the COOH terminus of H and containing the marker green fluorescent protein (GFP) gene in position 1. Two different H mutants were employed: H(SNS) (V451S, Y481N, and A527S)-CD46 blind, and H(AA) (Y481A and R533A)-CD46 and SLAM blind. MV-GFP virus was used as a positive control. Both EGFRvIII-retargeted viruses had significant antitumor activity against EGFRvIII-expressing glioblastoma multiforme but no cytopathic effect against normal cells. In an orthotopic model of EGFRvIII-expressing GBM39 xenografts, there was comparable therapeutic efficacy between retargeted strains and unmodified MV-GFP and statistically significant prolongation of survival in treated animals compared with the control group (P = 0.001). Formation of syncytia was observed in tumors treated with retargeted viruses, with a surrounding infiltrate consisting of macrophages and natural killer cells. In summary, EGFRvIII-retargeted oncolytic measles virus strains have comparable therapeutic efficacy with the unmodified MV-GFP strain against EGFRvIII-expressing glioma lines and xenografts with improved therapeutic index, a finding with potential translational implications in glioma virotherapy.
authors.affiliation: Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Allen
authors.forename: Sompong
authors.initials: S
authors.lastname: Vongpunsawad
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakamura
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Mark
authors.initials: M
authors.lastname: Schroeder
authors.forename: Roberto
authors.initials: R
authors.lastname: Cattaneo
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.forename: James
authors.initials: J
authors.lastname: Krempski
authors.forename: Kah-Whye
authors.initials: KW
authors.lastname: Peng
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Goble
authors.forename: Joon H
authors.initials: JH
authors.lastname: Uhm
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006224:Cricetinae; D017931:DNA Primers; D066246:ErbB Receptors / Q000235:genetics*; D017930:Genes, Reporter; D005910:Glioma / Q000276:immunology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008457:Measles / Q000235:genetics / Q000821:virology*; D008458:Measles Vaccine / Q000627:therapeutic use*; D008459:Measles virus / Q000276:immunology*; D014709:Vero Cells; D014764:Viral Proteins / Q000276:immunology
chemical_list: D017931:DNA Primers; D008458:Measles Vaccine; D014764:Viral Proteins; C410723:epidermal growth factor receptor VIII; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors