Optimizing Measles Virotherapy in the Treatment of Ovarian Cancer

描述(申请人提供)：卵巢癌是美国妇科癌症死亡的最常见原因，在美国每年约有16,000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。我们已经证明了工程麻疹病毒株对卵巢癌细胞株和异种移植瘤具有显著的抗肿瘤活性。它们的肿瘤特异性是由于麻疹病毒受体CD46在卵巢癌细胞中的大量表达。病毒一旦进入肿瘤细胞，就会导致与邻近细胞的膜融合，合胞体的形成和死亡。我们小组是第一个将这种方法转化为一种产生人类癌胚抗原的麻疹病毒衍生物MV-CEA(添加CEA以便于监测病毒基因表达)用于复发卵巢癌患者的I期临床试验。尽管病毒复制水平较低，部分患者的CEA水平略有上升就证明了这一点，但有希望的早期证据表明，抗肿瘤活性，包括CA-125降低和严重预治疗患者的疾病稳定时间延长。我们推测，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点：编码钠碘转运体(NIS)治疗性转基因的另一种麻疹病毒株MV-NIS，从而可以成像病毒在体内的分布并使用131I进行放射病毒治疗；使用受感染的细胞载体进行病毒传递；以及将麻疹病毒与具有免疫抑制和抗肿瘤特性的环磷酰胺相结合。因此，这项赠款计划的具体目标如下：1)在复发性卵巢癌患者中进行有限的I期腹腔注射MV-NIS试验；2)通过使用病毒感染的细胞载体，并测试具有抗肿瘤特性的免疫抑制药物环磷酰胺的额外益处，优化麻疹免疫小鼠ip麻疹病毒疗法对卵巢癌的疗效；3)测试静脉(IV)麻疹病毒疗法对卵巢癌的疗效，并通过使用病毒感染细胞载体，在麻疹免疫小鼠中优化其治疗效果，并在没有添加环磷酰胺的情况下；在优化注射或静脉注射后，131I放射病毒治疗的附加值也将得到测试。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，每年有1.6万名女性死于卵巢癌。我们小组正在开发一种新的方法来治疗卵巢癌，方法是使用在卵巢肿瘤中优先复制的麻疹病毒株。基于MV-CEA麻疹病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，在这项应用中，我们寻求优化病毒的传递和减弱对病毒的免疫反应，以提高治疗效果。此外，我们还测试了病毒株MV-NIS的潜力，这种病毒株可以对病毒在人体内的复制进行成像，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.