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

被引:77
作者
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
机构
[1] Mayo Clin, Program Mol Med, Rochester, MN 55905 USA
[2] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA
[3] Mayo Clin, Div Med Oncol, Rochester, MN 55905 USA
[4] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA
关键词
D O I
10.1158/0008-5472.CAN-06-1200
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Among the best-characterized genetic alterations in gliomas is the amplification of the epidermal growth factor receptor (EGFR) gene, present in similar to 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. NW-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 EGFRvIll-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 EGFRvIll-expressing glioma lines and xenograf. ts with improved therapeutic index, a finding with potential translational implications in glioma virotherapy.
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页码:11840 / 11850
页数:11
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