Measles Virus Therapy for Ovarian Cancer

卵巢癌是美国妇科癌症死亡的最常见原因，每年有超过1.4万人死于卵巢癌。复发的疾病仍然无法治愈，预后也很糟糕。迫切需要新的治疗药物。 MV-CEA是一种新型的病毒制剂，来源于梅奥临床癌症中心分子医学计划研发的埃德蒙斯顿麻疹疫苗株。该病毒已被改造成产生CEA，CEA可作为病毒基因表达的可跟踪标记，并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都具有显著的抗肿瘤潜力。 卵巢癌动物模型，而血清中的CEA水平代表了病毒基因表达的非常有用的相关性。 这项建议包括两个新概念：使用埃德蒙斯顿疫苗谱系的减毒麻疹病毒作为抗卵巢癌的抗肿瘤药物，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将是一种安全有效的治疗复发卵巢癌的药物。我们还假设，检测患者血清中的CEA可以作为跟踪病毒基因表达的有效手段，并可以在未来该试剂的应用中进行剂量优化。因此，我们建议在复发卵巢癌患者中进行MV-CEA的I期试验，目的如下：a)评估MV-CEA在复发卵巢癌患者中的安全性，并确定在这种情况下MV-CEA的最大耐受量；b)表征病毒基因图谱 目的：1)检测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水平和反应相关联；4)初步评估该方法的抗肿瘤疗效。

Ovarian cancer is the most common cause of gynecologic cancer deaths in the US and it is responsible for more than 14,000 deaths each year. Recurrent disease remains incurable and has a dismal prognosis. Novel therapeutic agents are urgently needed. MV-CEA is a novel viral agent deriving from the Edmonston's vaccine strain of measles virus, which was developed at the Molecular Medicine Program of the Mayo Clinic Cancer Center. 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 ovarian cancer animal models, while CEA levels in the serum represented a very helpful correlate of viral gene expression. This proposal includes two novel concepts: use of an attenuated measles virus of the Edmonston's vaccine lineage as an antitumor agent against ovarian cancer 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 ovarian cancer. We also hypothesize that detection of CEA in patients' serum can serve as an effective means of following viral gene expression and 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 ovarian cancer with the following objectives: a) to assess the safety of intraperitoneal administration of MV-CEA in patients with recurrent ovarian cancer 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 anti-tumor efficacy of this approach.