Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity
Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity
复制标题
DOI：
10.1158/0008-5472.can-06-1200
复制
发表时间：
2006-12-15
期刊：
影响因子：
11.2
通讯作者：
Galanis, Evanthia
中科院分区：
文献类型：
--
作者：
Allen, Cory;Vongpunsawad, Sompong;Galanis, Evanthia
胶质瘤中最典型的遗传改变是表皮生长因子受体(EGFR)基因的扩增，该基因存在于40%的多形性胶质母细胞瘤中，并经常与EGFRvIII基因重排有关。我们之前已经证明了麻疹病毒减毒疫苗株对胶质瘤具有强大的抗肿瘤活性，并发现了H蛋白突变，这些突变破坏了对天然麻疹病毒受体CD46和SLAM的识别。重定向重组病毒是从麻疹Edmonston-NSe疫苗株获得的，在H的COOH端显示了抗EGFRvIII的单链抗体，在第1位含有标志绿色荧光蛋白(GFP)基因。两个不同的H突变体：H-SNS(V451S、Y481N和A527S)-CD46和H-AA(Y481A和R533A)-CD46和SLAM盲。以NW-GFP病毒为阳性对照。两种EGFRvIII重定向病毒对表达EGFRvIII的多形性胶质母细胞瘤均有显着的抗肿瘤活性，但对正常细胞无细胞病变作用。在表达EGFRvI11基因的异种移植瘤模型中，重定向株与未修饰的MV-GFP具有相似的治疗效果，与对照组相比，处理组动物的存活时间显著延长(P=0.001)。在用重定向病毒治疗的肿瘤中观察到合胞体的形成，周围有由巨噬细胞和自然杀伤细胞组成的浸润物。综上所述，EGFRvIII重定向的溶瘤麻疹病毒株与未修饰的MV-GFP株对表达EGFRvIll的胶质瘤细胞和异种移植瘤具有相似的治疗效果。TS的治疗指数有所改善，这一发现在胶质瘤病毒治疗中具有潜在的翻译意义。
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.