Measles Virotherapy and radiovirotherapy in the Treatment of recurrent gliomas

麻疹病毒疗法和放射病毒疗法治疗复发性胶质瘤

基本信息

批准号：
8403544
负责人：
Evanthia Galanis
金额：
$ 30.9万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403544
关键词：
Accounting Adenoviruses Adult Animal Model Applications Grants Attenuated Vaccines Biodistribution CD46 Antigen Carcinoembryonic Antigen Cells Cessation of life Chemosensitization Clinic Clinical Clinical Trials Combined Modality Therapy Cyclophosphamide Data Diagnosis Disease Dose Engineering FDA approved Giant Cells Glioblastoma Glioma Gold Human Image Immune response Immune system Immunosuppressive Agents Inflammation Iodine Iodine Isotopes Isotopes Life Expectancy Macaca mulatta Malignant Glioma Malignant Neoplasms Measles Measles Vaccine Measles virus Mediating Membrane Fusion Methodology Monitor Morbidity - disease rate Mus Natural Immunity Oncolytic Patients Phase I Clinical Trials Positron-Emission Tomography Pre-Clinical Model Primary Brain Neoplasms Production Property Radioactive Iodine Radiovirotherapy Recurrence Rodent SLC5A5 gene Safety Schedule Sodium Surgically-Created Resection Cavity Technetium Testing Therapeutic Therapeutic Agents Time Toxic effect Toxicology Transgenic Mice Translating Viral Viremia Virus Virus Receptors Virus Replication Work Xenograft procedure adaptive immunity antitumor agent base efficacy testing experience follow-up in vivo innovation neoplastic cell neurotoxicity novel novel strategies novel therapeutics oncolysis outcome forecast pre-clinical preclinical efficacy public health relevance research study single photon emission computed tomography symporter therapeutic transgene tumor tumor specificity vector

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, accounting for most of 18,500 primary brain tumor cases each year in the US. Prognosis is dismal with a median survival of 12-15 mo, despite use of multimodality treatment. Novel therapeutic agents are urgently needed. Our group was the first to demonstrate that engineered measles virus (MV) strains have significant antitumor activity against gliomas. Their tumor specificity is due to abundant expression of the MV receptor CD46 in glioma cells. The virus upon entry in the tumor cells, causes membrane fusion with neighboring cells, syncytia formation and death. In addition, we have translated this approach into the first human clinical trial of a measles virus derivative producing human carcinoembryonic antigen, MV-CEA (CEA added to facilitate viral monitoring) in recurrent GBM patients. We now hypothesize that by introducing a therapeutic transgene and suppressing the innate immune response, we can further augment the antitumor activity of measles virotherapy in gliomas. We propose to accomplish this by testing the translational potential of three novel approaches in glioma treatment; a different measles virus strain, MV-NIS, which encodes the sodium iodine symporter (NIS) gene, thus allowing imaging of viral distribution in vivo; enhancing MV-NIS oncolysis, by exploiting NIS as therapeutic transgene with application of the beta and gamma emitter 131I (radiovirotherapy); and combining measles virus derivatives with cyclophosphamide, an agent that has been shown to suppress anti-viral innate and adaptive immunity, and increase viral proliferation in tumors. This grant proposal has therefore the following specific aims: 1) to test the efficacy of radiovirotherapy with MV-NIS in GBM lines and xenografts, compare it with MV-CEA and investigate the mechanism of antitumor activity; 2) to further increase the potency of measles virotherapy or radiovirotherapy by combining measles derivatives with cyclophosphamide (CPA), and optimize CPA's dose and schedule in this context; 3) to study viral biodistribution, interaction with the immune system and safety following intracranial administration, in two measles replication permissive animal models, Ifnarko CD46 Ge transgenic mice and Rhesus macaques.

描述（由申请人提供）：多形胶质母细胞瘤（GBM）是成年人中最常见的原发性脑肿瘤，在美国，每年18,500例原发性脑肿瘤病例中的大部分。尽管使用了多模态治疗，但预后的中位生存率为12-15 mo。迫切需要新颖的治疗剂。我们的小组是第一个证明工程麻疹病毒（MV）菌株具有对神经胶质瘤的显着抗肿瘤活性。它们的肿瘤特异性是由于MV受体CD46在神经胶质瘤细胞中的大量表达所致。进入肿瘤细胞后的病毒会导致膜融合与相邻细胞，合成症形成和死亡。此外，我们将这种方法转化为麻疹病毒衍生物的首次人类临床试验，该试验产生了人类癌症抗原，MV-CEA（添加以促进病毒监测）在复发性GBM患者中。现在，我们假设通过引入治疗转基因并抑制先天免疫反应，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型神经胶质瘤治疗方法的翻译潜力来实现这一目标。不同的麻疹菌株MV-NIS，它编码碘的碘分类蛋白（NIS）基因，从而允许体内病毒分布的成像；通过应用Beta和Gamma Emitter 131i（放射性疗法）利用NIS作为治疗转基因来增强MV-nis oncolysis；并将麻疹病毒衍生物与环磷酰胺相结合，这种药物已被证明可抑制抗病毒先天和适应性免疫，并增加肿瘤中的病毒增殖。因此，该赠款提案具有以下具体目的：1）测试用MV-NIS在GBM系和异种移植物中进行放射电动疗法的功效，将其与MV-CEA进行比较并研究抗肿瘤活性的机理； 2）通过将麻疹衍生物与环磷酰胺（CPA）相结合，并在这种情况下优化CPA的剂量和时间表，以进一步提高麻疹病毒疗法或放射治疗的效力； 3）在两种麻疹复制允许的动物模型中，研究病毒生物分布，与免疫系统的相互作用和颅内给药后的安全性，Ifnarko CD46 GE转基因小鼠和恒河猴。