Optimizing Measles Virotherapy in the Treatment of Ovarian Cancer

描述（由申请人提供）：卵巢癌是美国妇科癌症死亡的最常见原因，每年约有16，000人死于卵巢癌。复发性疾病仍然无法治愈，预后很差。迫切需要新的治疗剂。我们已经证明，工程麻疹病毒株对卵巢癌细胞系和异种移植物具有显着的抗肿瘤活性。它们的肿瘤特异性是由于麻疹病毒受体CD 46在卵巢癌细胞中的大量表达。病毒进入肿瘤细胞后，引起与邻近细胞的膜融合、合胞体形成和死亡。我们的小组是第一个将这种方法转化为麻疹病毒衍生物生产人类癌胚抗原MV-CEA（CEA添加以促进监测病毒基因表达）的I期临床试验的复发性卵巢癌患者。尽管病毒复制水平较低，如在一个亚组的患者中CEA适度升高所证明的那样，但有希望的抗肿瘤活性的早期证据，包括在大量预治疗的患者中CA-125降低和疾病稳定期延长。我们推测，通过增加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疗法在卵巢癌中的抗肿瘤活性。我们建议通过测试三种新方法的翻译潜力来实现这一目标：一种不同的麻疹病毒株MV-NIS，它编码碘化钠同向转运体（NIS）治疗转基因，从而允许体内病毒分布成像和131 I用于放射病毒治疗;使用感染的细胞载体进行病毒递送;以及将麻疹病毒与环磷酰胺结合，环磷酰胺是一种具有免疫抑制和抗肿瘤特性的药剂。因此，该拨款提案具有以下具体目标：1）在复发性卵巢癌患者中进行MV-NIS腹膜内（IP）施用的有限I期试验; 2）通过使用病毒感染的细胞载体，并测试环磷酰胺（一种具有抗肿瘤特性的免疫抑制药物）的额外益处，优化IP麻疹病毒疗法对麻疹免疫小鼠中卵巢癌的功效; 3）测试静脉内（IV）麻疹病毒疗法对卵巢癌的功效，并通过使用病毒感染的细胞载体在添加和不添加环磷酰胺的情况下在麻疹免疫小鼠中优化该疗法;在优化IP或IV递送之后，还将测试131 I放射病毒疗法的附加值。公共卫生相关性：卵巢癌是美国妇科癌症死亡的最常见原因，每年造成16，000名妇女死亡。我们的研究小组正在开发一种新的方法，通过使用优先在卵巢肿瘤中复制的麻疹病毒株来治疗卵巢癌。基于MV-CEA麻疹毒株在复发性卵巢癌患者中的I期试验获得的有希望的数据，在本申请中，我们寻求优化病毒的递送并减弱针对病毒的免疫应答，以提高治疗效果。此外，我们测试了MV-NIS病毒株的潜力，该病毒株允许对人体内的病毒复制进行成像，并使用放射性碘来增强治疗效果。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Ovarian cancer is the most common cause of gynecologic cancer death in the United States, and it is responsible for the deaths of 16,000 women each year. Our group is developing a novel approach to treat ovarian cancer by using measles virus strains that preferentially replicate in ovarian tumors. Based on promising data deriving from a phase I trial of the MV-CEA measles strain in recurrent ovarian cancer patients, in this application we seek to optimize delivery of the virus and weaken the immune response against the virus in order to increase the efficacy of the treatment. Furthermore, we test the potential of the viral strain MV-NIS, which allows imaging of the viral replication in the human body and use of radioactive iodine to augment the therapeutic effect.