Optimizing Measles Virotherapy in the Treatment of Ovarian Cancer

项目总结/摘要 卵巢癌是美国妇科癌症死亡的最常见原因， 美国每年约有16,000人死亡。复发性疾病仍然无法治愈， 预后迫切需要新的治疗剂。 我们已经证明，工程麻疹病毒株具有显着的抗肿瘤活性， 卵巢癌细胞系和异种移植物。它们的肿瘤特异性是由于麻疹病毒的大量表达 卵巢癌细胞中的CD 46受体。病毒进入肿瘤细胞后，引起细胞膜融合， 相邻细胞、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阶段的团队 产生人癌胚抗原的麻疹病毒衍生物MV-CEA（添加CEA）的临床试验 以便于监测病毒基因表达）。尽管病毒水平很低 复制，如在一个亚组的患者中CEA适度升高所证明的那样， 抗肿瘤活性的证据，包括CA-125降低和延长疾病稳定的严重 预处理的患者。我们假设通过增加肿瘤细胞感染的效率和程度， 进一步增强麻疹病毒疗法在卵巢癌中的抗肿瘤活性。我们建议实现 这是通过测试三种新方法的翻译潜力来实现的：一种不同的麻疹病毒株，MV-NIS， 其编码钠碘同向转运体（NIS）治疗转基因，从而允许病毒成像。 体内分布和131 I用于放射病毒治疗的用途;感染的细胞载体用于病毒递送的用途;以及， 将麻疹病毒与环磷酰胺结合，免疫抑制剂和抗肿瘤剂 特性. 因此，这项赠款建议有以下具体目标：1）进行有限的第一阶段试验， 复发性卵巢癌患者腹腔内（IP）给予MV-NIS; 2）优化 麻疹病毒感染细胞腹腔注射治疗麻疹免疫小鼠卵巢癌疗效观察 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， 性质; 3）测试静脉内（IV）麻疹病毒疗法对卵巢癌的疗效，并优化其在 用病毒感染的细胞载体免疫小鼠，加和不加环磷酰胺; 在优化IP或IV输送后，还将测试131 I放射病毒治疗的附加值。

PROJECT SUMMARY/ABSTRACT 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. 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 monitoring of viral gene expression) in recurrent ovarian cancer patients. Despite low levels of viral replication, as evidenced by modest CEA elevation in a subgroup 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-NIS, which encodes the Sodium Iodide Symporter (NIS) therapeutic transgene, thus allowing imaging of viral distribution in vivo and use of 131I 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 I 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 131I radiovirotherapy will also be tested.