Optimizing Measles Virotherapy in the Treatment of Recurrent Ovarian Cancer

卵巢癌是美国妇科癌症死亡的最常见原因，也是 在美国，每年约有16,000人死亡。反复发作的疾病仍然无法治愈，并有令人沮丧的 预后。迫切需要新的治疗药物。 我们已经证明，工程麻疹病毒株具有显著的抗肿瘤活性。 卵巢癌细胞系和异种移植瘤。它们的肿瘤特异性是由于麻疹的大量表达 卵巢癌细胞中的病毒受体CD46。病毒一旦进入肿瘤细胞，就会引起膜融合。 与邻近细胞、合胞体形成和死亡。我们的团队是第一个将这种方法转化为 产生人类癌胚抗原的麻疹病毒衍生物MV-CEA(CEA)的I期临床试验 添加以便于病毒监测)的复发卵巢癌患者。尽管病毒复制水平很低， 少数患者的CEA轻度升高证明了这一点，早期证据显示 包括CA-125在内的抗肿瘤活性降低并延长病情稳定时间 病人。我们假设，通过提高肿瘤细胞感染的效率和程度，我们可以进一步 增强麻疹病毒治疗卵巢癌的抗肿瘤活性。我们建议通过以下方式实现这一目标 测试三种新方法的翻译潜力：一种不同的麻疹病毒株MV-NLS，它 编码钠碘转运体(NIS)治疗性转基因，从而可以对病毒分布进行成像 在体内和使用^^1进行放射病毒治疗；使用受感染的细胞载体进行病毒传递；以及，结合 麻疹病毒与环磷酰胺，一种具有免疫抑制和抗肿瘤特性的药物。 因此，这项赠款提案有以下具体目标：1)进行有限的第一阶段试验 腹膜腔内注射MV-NIS治疗复发性卵巢癌2)优化 病毒感染的麻疹免疫小鼠ip麻疹病毒治疗卵巢癌的疗效 细胞载体，并测试环磷酰胺的额外益处，环磷酰胺是一种具有抗肿瘤作用的免疫抑制药物 3)检测静脉注射麻疹病毒治疗卵巢癌的疗效，并对其进行优化。 在麻疹免疫小鼠中，使用病毒感染的细胞载体，并添加和不添加环磷酰胺； 在优化IP或IV递送后，^^1放射病毒疗法的附加值也将进行测试和4)至 将最有希望的方法转化为复发性卵巢癌患者的1期试验。 相关性(请参阅说明)： 卵巢癌是美国妇科癌症死亡的最常见原因，也是 在美国，每年大约有16,000人死亡。麻疹疫苗株在临床前有重要意义 对卵巢癌的抗肿瘤活性和最近完成的一项腹膜内I期试验 接种麻疹病毒株MV-CEA显示了良好的早期生物活性。此应用程序 建议研究策略，进一步优化麻疹疫苗株作为新型抗肿瘤药物的使用 治疗卵巢癌的药物。

Ovarian cancer is the most common cause of gynecologic cancer death in the U.S. and is responsible for approximately 16,000 deaths each year in the U.S. Recurrent disease remains incurable and has a dismal prognosis. Novel therapeutic agents are urgently needed. We have demonstrated that engineered measles virus strains have significant antitumor activity against ovarian cancer lines and xenografts. Their tumor specificity is due to abundant expression of the measles virus receptor CD46 in ovarian cancer cells. The virus, upon entry into tumor cells, causes membrane fusion with neighboring cells, syncytia formation and death. Our group was the first to translate this approach into a phase I clinical trial of a measles virus derivative producing human carcinoembryonic antigen, MV-CEA (CEA added to facilitate viral monitoring) in recurrent ovarian cancer patients. Despite low levels of viral replication, as evidenced by modest CEA elevation in a minority of patients, there was promising early evidence of antitumor activity, including CA-125 decreases and prolonged disease stabilization in heavily pretreated patients. We hypothesize that by increasing the efficiency and extent of tumor cell infection we can further augment the antitumor activity of measles virotherapy in ovarian cancer. We propose to accomplish this by testing the translational potential of three novel approaches: a different measles virus strain, MV-NlS, which encodes the Sodium Iodide Symporter (NIS) therapeutic transgene, thus allowing imaging of viral distribution in vivo and use of ^^^1 for radiovirotherapy; use of infected cell carriers for viral delivery; and, combining the measles virus with cyclophosphamide, an agent with immunosuppressive and antitumor properties. This grant proposal has, therefore, the following specific aims, 1) to perform a limited phase 1 trial of intraperitoneal (IP) administration of MV-NIS in patients with recurrent ovarian cancer; 2) to optimize the efficacy of IP measles virotherapy for ovarian cancer in measles immune mice by employing virus infected cell carriers, and testing the added benefit of cyclophosphamide, an immunosuppressive drug with antitumor properties; 3) to test the efficacy of intravenous (IV) measles virotherapy for ovarian cancer, and optimize it in measles immune mice by using virus infected cell carriers, with and without addition of cyclophosphamide; following optimization of IP or IV delivery the added value of ^^^1 radiovirotherapy will also be tested and 4) to translate the most promising approach to a phase 1 trial in patients with recurrent ovarian cancer. RELEVANCE (See instructions): Ovarian cancer is the most common cause of gynecologic cancer death in the U.S. and is responsible for approximately 16,000 deaths each year in the US. Measles vaccine strains have significant preclinical antitumor activity against ovarian cancer, and a recently completed phase I trial of intraperitoneal administration of the measles strain MV-CEA indicates promising early biologic activity. This application proposes to investigate strategies to further optimize the use of measles vaccine strains as novel antitumor agents in the treatment of ovarian cancer.