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，在美国每年约有16,000人死亡。复发性疾病仍然无法治愈，预后不佳。迫切需要新的治疗药物。我们已经证明，工程麻疹病毒株对卵巢癌系和异种移植物具有显著的抗肿瘤活性。它们的肿瘤特异性是由于在卵巢癌细胞中大量表达麻疹病毒受体CD46。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。我们的团队率先将这种方法转化为一种麻疹病毒衍生物的I期临床试验，该病毒衍生物在复发性卵巢癌患者中产生人癌胚抗原MV-CEA（添加CEA以促进病毒基因表达的监测）。尽管低水平的病毒复制，如在一个亚组患者中适度的CEA升高所证明的那样，有希望的抗肿瘤活性的早期证据，包括在大量预处理的患者中CA-125降低和延长疾病稳定。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。我们建议通过测试三种新方法的转化潜力来实现这一目标：一种不同的麻疹病毒株，MV-NIS，它编码碘化钠同体转运蛋白（NIS）治疗转基因，从而允许在体内成像病毒分布并使用131I进行放射病毒治疗；利用受感染的细胞载体传递病毒；并将麻疹病毒与环磷酰胺联合使用，环磷酰胺是一种具有免疫抑制和抗肿瘤特性的药物。因此，该资助提案有以下具体目的：1)对复发性卵巢癌患者进行腹腔注射MV-NIS的有限I期试验；2)利用病毒感染的细胞载体，优化IP麻疹病毒治疗麻疹免疫小鼠卵巢癌的疗效，并检测具有抗肿瘤特性的免疫抑制药物环磷酰胺的附加效益；3)检测静脉注射（IV）麻疹病毒治疗卵巢癌的疗效，并在麻疹免疫小鼠中采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进行优化；优化IP或IV给药后，131I放射病毒治疗的附加价值也将被测试。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，每年导致16,000名妇女死亡。我们的团队正在开发一种治疗卵巢癌的新方法，利用麻疹病毒株在卵巢肿瘤中优先复制。基于在复发性卵巢癌患者中进行的MV-CEA麻疹毒株I期试验的有希望的数据，在本应用中，我们寻求优化病毒的递送并减弱对病毒的免疫反应，以提高治疗效果。此外，我们测试了病毒株MV-NIS的潜力，它可以成像病毒在人体内的复制，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.