Optimizing Measles Virotherapy in the Treatment of Gliomas

多形性胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤，占大多数 美国每年有18,000例原发性脑肿瘤病例。预后很差，中位生存期为12-15 尽管使用了多模式治疗，但无一例死亡。迫切需要新的治疗剂。于本 在马约脑孢子项目的资助期间，我们的团队是第一个证明工程麻疹的人 病毒（MV）株对神经胶质瘤具有显著的抗肿瘤活性。它们的肿瘤特异性是由于 MV受体CD 46在胶质瘤细胞中的丰富表达。病毒进入肿瘤细胞后， 引起与邻近细胞的膜融合、合胞体形成和死亡。另外我们有 将这种方法转化为麻疹病毒衍生物产生人类的第一次人类临床试验， 癌胚抗原MV-CEA（添加CEA以促进病毒监测）在复发性GBM患者中的应用。我们 现在假设，通过增加肿瘤细胞破坏的效率和程度，并通过引入 治疗性转基因，我们可以进一步增强麻疹病毒疗法在胶质瘤中的抗肿瘤活性。我们 我建议通过测试三种新方法的翻译潜力来实现这一目标;一种不同的 麻疹病毒株，MV-NIS，它编码钠碘同向转运体（NIS）基因，从而允许成像 通过利用NIS作为治疗性转基因， β和γ发射器的应用

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, accounting for most of 18,000 primary brain tumor cases each year in the US. Prognosis is dismal with a median survival of 12-15 mo, despite use of multimodality treatment. Novel therapeutic agents are urgently needed. During the current funding period of the Mayo Brain SPORE, our group was the first to demonstrate that engineered measles virus (MV) strains have significant antitumor activity against gliomas. Their tumor specificity is due to abundant expression of the MV receptor CD46 in glioma cells. The virus upon entry in the tumor cells, causes membrane fusion with neighboring cells, syncytia formation and death. In addition, we have translated this approach into the first human clinical trial of a measles virus derivative producing human carcinoembryonic antigen, MV-CEA (CEA added to facilitate viral monitoring) in recurrent GBM patients. We now hypothesize that by increasing the efficiency and extent of tumor cell destruction and by introducing a therapeutic transgene, we can further augment the antitumor activity of measles virotherapy in gliomas. We propose to accomplish this by testing the translational potential of three novel approaches; a different measles virus strain, MV-NIS, which encodes the sodium iodine symporter (NIS) gene, thus allowing Imaging of viral distribution in vivo; enhancing MV-NIS oncolysis, by exploiting NIS as therapeutic transgene with application of the beta and gamma emitter