Measles Virotherapy for Glioblastoma Multiforme

描述(申请人提供)：多形性胶质母细胞瘤是最常见的成人原发脑瘤，在美国每年确诊的18,500例原发脑瘤中占大多数。尽管进行了多种治疗，它的预后很差，中位生存期为12-15个月。迫切需要新的治疗药物。MV-CEA是一种来源于麻疹病毒埃德蒙顿疫苗株的新型病毒制剂。该病毒已被改造成产生CEA，CEA作为病毒基因表达的可跟踪标记，可用于监测体内的病毒治疗。在临床前工作中，我们已经证明了该病毒在体外和体内对胶质母细胞瘤动物模型的显著抗肿瘤潜力，而血清中CEA水平代表了病毒基因表达的有用相关性。这项建议包括两个新的概念：使用埃德蒙顿疫苗谱系的减毒麻疹病毒作为抗肿瘤药物来对抗复发的多形性胶质母细胞瘤，以及使用一种新的跟踪系统，可以显著提高我们监督病毒治疗试验的能力。我们的假设是MV-CEA将是治疗复发性多形性胶质母细胞瘤的一种安全有效的药物。我们还假设，患者血清中CEA的检测可以作为跟踪病毒基因表达的有效手段，这可能使该试剂在未来的应用中进行剂量优化。因此，我们建议在复发性多形性胶质母细胞瘤患者中进行MV-CEA的I期试验，目标如下：a)评估MV-CEA在复发性多形性胶质母细胞瘤患者瘤内和切除腔内应用的安全性，并确定在这种情况下MV-CEA的最大耐受量；b)表征血清CEA浓度所表现的每个剂量水平的病毒基因表达情况，评估病毒血症、病毒复制和麻疹病毒的脱落和持久性；c)确定对注射病毒的体液和细胞免疫反应，并将其与毒性、病毒血症、CEA水平和应答相关联；以及d)初步评估该方法的抗肿瘤活性。

DESCRIPTION (provided by applicant): Glioblastoma multiforme is the most common primary brain tumor in adults, accounting for the majority of 18,500 cases of primary brain tumors diagnosed each year in the U.S. It has a dismal prognosis with a 12- 15 month median survival despite multimodality treatment. Novel therapeutic agents are urgently needed. MV-CEA is a novel viral agent deriving from the Edmonton vaccine strain of measles virus. The virus has been engineered to produce CEA that serves as a trackable marker of viral gene expression and can be used for monitoring of viral therapy in vivo. In preclinical work we have demonstrated significant antitumor potential of the virus, both in vitro and in vivo against glioblastoma animal models while CEA levels in the serum represent a helpful correlate of viral gene expression. This proposal includes two novel concepts: use of an attenuated measles virus of the Edmonton vaccine lineage as an antitumor agent against recurrent glioblastoma multiforme and use of a novel tracking system that could significantly improve our ability to monitor virotherapy trials. Our hypothesis is that MV-CEA will be a safe and effective agent for treatment of recurrent glioblastoma multiforme. We also hypothesize that the detection of CEA in patient serum can serve as an effective means of following viral gene expression, which could allow dose optimization in future applications of this agent. Therefore, we propose to conduct a phase I trial of MV-CEA in patients with recurrent glioblastoma multiforme with the following objectives: a) to assess the safety of intratumoral and resection cavity administration of MV-CEA in patients with recurrent glioblastoma multiforme and to determine the maximum tolerated dose of MV-CEA in this setting; b) to characterize the profile of viral gene expression at each dose level as manifested by the serum CEA concentrations and to assess viremia, viral replication, and measles virus shedding and persistence; c) to determine humoral and cellular immune response to the injected virus and correlate it with toxicity, viremia, CEA levels, and response; and d) to assess in a preliminary fashion the antitumor activity of this approach.