Measles Virotherapy and radiovirotherapy in the Treatment of recurrent gliomas

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人最常见的原发性脑肿瘤，在美国每年18500例原发性脑肿瘤病例中占大多数。尽管采用了多模式治疗，但预后惨淡，中位生存期为12-15个月。迫切需要新的治疗药物。我们的小组是第一个证明工程麻疹病毒（MV）株对胶质瘤有显著的抗肿瘤活性。它们的肿瘤特异性是由于在胶质瘤细胞中大量表达MV受体CD46。病毒进入肿瘤细胞后，与邻近细胞膜融合，形成合胞体并死亡。此外，我们已经将这种方法转化为麻疹病毒衍生物在复发性GBM患者中产生人癌胚抗原MV-CEA（添加CEA以促进病毒监测）的首次人体临床试验。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治疗在胶质瘤中的抗肿瘤活性。我们建议通过测试胶质瘤治疗中三种新方法的转化潜力来实现这一目标；另一种麻疹病毒株MV-NIS，它编码碘同转运体钠（NIS）基因，从而可以对病毒在体内的分布进行成像；利用NIS作为治疗性转基因，应用β和γ发射器131I（放射病毒疗法），增强MV-NIS肿瘤溶解；并将麻疹病毒衍生物与环磷酰胺结合，环磷酰胺是一种抑制抗病毒先天免疫和适应性免疫的药物，并增加肿瘤中的病毒增殖。因此，本项目有以下具体目的：1)测试MV-NIS放射病毒治疗GBM系和异种移植物的疗效，将其与MV-CEA进行比较，并研究其抗肿瘤活性的机制；2)通过麻疹衍生物与环磷酰胺（cyclophosphamide， CPA）联用进一步提高麻疹病毒治疗或放射病毒治疗的效力，并优化CPA的剂量和方案；3)在Ifnarko CD46 Ge转基因小鼠和恒河猴两种麻疹复制许可动物模型中研究病毒的生物分布、与免疫系统的相互作用以及颅内给药后的安全性。

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.