Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity

Cory Allen, Sompong Vongpunsawad, Takafumi Nakamura, C. David James, Mark Schroeder, Roberto Cattaneo, Caterina Giannini, James Krempski, Kah-Whye Peng, Jenny M. Goble, Joon H. Uhm, Stephen J Russell, Evanthia Galanis

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Abstract

Among the best-characterized genetic alterations in gliomas is the amplification of the epidermal growth factor receptor (EGFR) gene, present in ∼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 HAA (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.

Original languageEnglish (US)
Pages (from-to)11840-11850
Number of pages11
JournalCancer Research
Volume66
Issue number24
DOIs
StatePublished - Dec 15 2006

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Measles
Glioma
Green Fluorescent Proteins
Measles virus
Neoplasms
Viruses
Glioblastoma
Heterografts
Oncolytic Viruses
erbB-1 Genes
Virus Receptors
Single-Chain Antibodies
Attenuated Vaccines
Gene Order
Gene Rearrangement
Giant Cells
epidermal growth factor receptor VIII
Natural Killer Cells
Therapeutics
Vaccines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity. / Allen, Cory; Vongpunsawad, Sompong; Nakamura, Takafumi; James, C. David; Schroeder, Mark; Cattaneo, Roberto; Giannini, Caterina; Krempski, James; Peng, Kah-Whye; Goble, Jenny M.; Uhm, Joon H.; Russell, Stephen J; Galanis, Evanthia.

In: Cancer Research, Vol. 66, No. 24, 15.12.2006, p. 11840-11850.

Research output: Contribution to journalArticle

Allen, Cory ; Vongpunsawad, Sompong ; Nakamura, Takafumi ; James, C. David ; Schroeder, Mark ; Cattaneo, Roberto ; Giannini, Caterina ; Krempski, James ; Peng, Kah-Whye ; Goble, Jenny M. ; Uhm, Joon H. ; Russell, Stephen J ; Galanis, Evanthia. / Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity. In: Cancer Research. 2006 ; Vol. 66, No. 24. pp. 11840-11850.
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AU - Allen, Cory

AU - Vongpunsawad, Sompong

AU - Nakamura, Takafumi

AU - James, C. David

AU - Schroeder, Mark

AU - Cattaneo, Roberto

AU - Giannini, Caterina

AU - Krempski, James

AU - Peng, Kah-Whye

AU - Goble, Jenny M.

AU - Uhm, Joon H.

AU - Russell, Stephen J

AU - Galanis, Evanthia

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N2 - Among the best-characterized genetic alterations in gliomas is the amplification of the epidermal growth factor receptor (EGFR) gene, present in ∼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 HAA (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.

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