Measles Virotherapy and radiovirotherapy in the Treatment of recurrent gliomas

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是成人最常见的原发脑瘤，占美国每年18,500例原发脑瘤的大部分。预后很差，中位生存期为12-15个月，尽管采用了多种治疗方法。迫切需要新的治疗药物。本课题组首次证实麻疹工程病毒(MV)株对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CD46在胶质瘤细胞中的大量表达。病毒一旦进入肿瘤细胞，就会引起与邻近细胞的膜融合、合胞体的形成和死亡。此外，我们已经将这种方法转化为产生人类癌胚抗原的麻疹病毒衍生物MV-CEA(添加CEA以便于病毒监测)在复发的GBM患者中的第一次人类临床试验。我们现在假设，通过引入治疗性转基因和抑制先天免疫反应，我们可以进一步增强麻疹病毒疗法对胶质瘤的抗肿瘤活性。我们建议通过测试三种新方法在胶质瘤治疗中的翻译潜力来实现这一点；另一种麻疹病毒株MV-NIS编码钠碘转运体(NIS)基因，从而能够成像病毒在体内的分布；通过将NIS用作治疗性转基因并应用贝塔和伽马发射体131I(放射病毒疗法)来增强MV-NIS肿瘤分解；以及将麻疹病毒衍生物与环磷酰胺相结合，环磷酰胺已被证明可以抑制抗病毒的固有免疫和获得性免疫，并促进病毒在肿瘤中的增殖。因此，这项拨款建议有以下具体目的：1)测试MV-NIS对GBM细胞和异种移植瘤的放射病毒治疗效果，并与MV-CEA进行比较，探讨其抗肿瘤作用机制；2)通过将麻疹衍生物与环磷酰胺(CPA)联合使用，进一步提高麻疹病毒治疗或放射病毒治疗的效力，并在此背景下优化CPA的剂量和时间；3)在两种麻疹复制允许复制的动物模型(Ifnarko CD46 GE转基因小鼠和恒河猴)中，研究病毒的生物分布、与免疫系统的相互作用和安全性。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, accounting for most of 18,500 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. 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 introducing a therapeutic transgene and suppressing the innate immune response, 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 in glioma treatment; 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 131I (radiovirotherapy); and combining measles virus derivatives with cyclophosphamide, an agent that has been shown to suppress anti-viral innate and adaptive immunity, and increase viral proliferation in tumors. This grant proposal has therefore the following specific aims: 1) to test the efficacy of radiovirotherapy with MV-NIS in GBM lines and xenografts, compare it with MV-CEA and investigate the mechanism of antitumor activity; 2) to further increase the potency of measles virotherapy or radiovirotherapy by combining measles derivatives with cyclophosphamide (CPA), and optimize CPA's dose and schedule in this context; 3) to study viral biodistribution, interaction with the immune system and safety following intracranial administration, in two measles replication permissive animal models, Ifnarko CD46 Ge transgenic mice and Rhesus macaques.