Optimizing Measles Virotherapy in the Treatment of Ovarian Cancer

优化麻疹病毒疗法治疗卵巢癌

• 批准号: 8061636
• 负责人: Evanthia Galanis
• 金额: $ 42.42万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061636
• 关键词: Abdominal Cavity; Address; Adhesions; Antibodies; Antiviral Agents; Apoptotic; Applications Grants; CA-125 Antigen; CD46 Antigen; Cancer Model; Cancer Patient; Carcinoembryonic Antigen; Catheters; Cell Line; Cells; Cessation of life; Clinical; Complement; Cyclophosphamide; Cytolysis; Data; Diffusion; Disease; Dose; Engineering; Gamma Cameras; Gene Expression; Genes; Giant Cells; Greater sac of peritoneum; Gynecologic; Health; Human; Human body; Image; Immune; Immune response; Immunity; Immunosuppressive Agents; Infection; Intravenous; Iodine; Iodine Isotopes; Isotopes; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measles; Measles virus; Mediating; Membrane Fusion; Mesenchymal Stem Cells; Monitor; Morbidity - disease rate; Multiple Myeloma; Mus; Nude Mice; Oncolytic; Oncolytic viruses; Ovarian; Patients; Peptides; Peritoneal; Peritoneal Fluid; Personal Communication; Pharmaceutical Preparations; Phase I Clinical Trials; Process; Property; Radioactive Iodine; Recurrence; Recurrent disease; SLC5A5 gene; Safety; Saimiri; Serum; Simplexvirus; Site; Sodium; Specificity; Stable Disease; Structure; Subgroup; Technetium; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Uses; Transgenes; Translating; Treatment Efficacy; United States; Viral; Viral Genes; Virus; Virus Receptors; Woman; Xenograft procedure; base; cancer cell; cancer therapy; efficacy testing; gene therapy; improved; in vivo; innovation; intraperitoneal; intravenous administration; neoplastic cell; novel; novel strategies; novel therapeutics; outcome forecast; ovarian neoplasm; overexpression; patient population; research clinical testing; research study; response; single photon emission computed tomography; sodium-iodide symporter; symporter; therapeutic transgene; tissue culture; tumor; tumor specificity

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.

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，预后却令人沮丧。迫切需要新颖的治疗剂。我们已经证明，工程麻疹病毒菌株具有针对卵巢癌系和异种移植物的显着抗肿瘤活性。它们的肿瘤特异性是由于麻疹受体CD46在卵巢癌细胞中的大量表达所致。该病毒进入肿瘤细胞后，会导致膜融合与邻近细胞，合成症形成和死亡。我们的小组是第一个将这种方法转化为麻疹病毒衍生物的I期临床试验，该试验产生了人类癌症抗原，MV-CEA，MV​​-CEA（CEA添加以促进复发性卵巢癌患者监测病毒基因表达）。尽管病毒复制水平较低，但患者亚组的CEA升高证明了，但有希望的早期证据表明抗肿瘤活性，包括CA-125降低和长期预处理的患者疾病稳定。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疗法的抗肿瘤活性。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菌株MV-NIS，它编码碘化钠分类剂（NIS）治疗转基因，从而允许体内病毒分布的成像和131i的使用。使用感染的细胞载体进行病毒递送；并且，将麻疹病毒与环磷酰胺（具有免疫抑制和抗肿瘤特性的药物）结合在一起。因此，该赠款提案具有以下具体目的，即1）在复发性卵巢癌患者中对MV-NIS进行I阶段的I期有限试验； 2）通过采用病毒感染的细胞载体来优化卵巢癌在麻疹免疫小鼠中的病毒疗法的功效，并测试环磷酰胺的附加益处，环磷酰胺是具有抗肿瘤特性的免疫抑制药物； 3）测试静脉内（IV）麻疹病毒疗法对卵巢癌的疗效，并通过使用病毒感染的细胞载体在麻疹免疫小鼠中对其进行优化，而有或不加入环磷酰胺；在优化IP或IV递送后，还将测试131i放射治疗的附加值。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。我们的小组正在通过使用优先在卵巢肿瘤中复制的麻疹病毒菌株来开发一种治疗卵巢癌的新方法。基于从复发性卵巢癌患者的MV-CEA麻疹菌株I期试验中得出的有希望的数据，在此应用中，我们试图优化病毒的输送并削弱针对病毒的免疫反应，以提高治疗的功效。此外，我们测试了病毒菌株MV-NI的潜力，该病毒菌株允许对人体中的病毒复制进行成像，并使用放射性碘以增强治疗效果。