Phase I Clinical Translation Trial of Oncolytic rVSV-F Virotherapy for HCC

溶瘤 rVSV-F 病毒疗法治疗 HCC 的 I 期临床转化试验

• 批准号: 7667824
• 负责人: Savio L Woo
• 金额: $ 48.72万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-16 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667824
• 关键词: Acute; Animals; Antiviral Response; Attenuated; Cancer Etiology; Cells; Cessation of life; Child; Clinical; Cyclic GMP; Development; Dose; Etiology; Future; Hepatic; Hepatic artery; Hepatitis B Virus; Hepatitis C virus; Hepatitis Viruses; Hepatocyte; Human; Immune; In Vitro; Infusion procedures; Laboratory Finding; Lead; Lesion; Liver; Liver diseases; Liver neoplasms; Macaca mulatta; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Membrane Glycoproteins; Newcastle disease virus; Oncolytic; Pathology; Patients; Pharmacology and Toxicology; Phase; Primary carcinoma of the liver cells; RNA Viruses; Rattus; Recombinants; Refractory; Resectable; Resected; Residual state; Safety; Sampling; Series; Slice; Specificity; Specimen; Survival Rate; Testing; Time; Tissues; Toxic effect; Translating; Translational Research; Translations; Vesicular stomatitis Indiana virus; Viral; Viral hepatitis; Virus; Virus Diseases; Virus Replication; artery infusion; cGMP production; cancer therapy; clinical lot; liver function; neoplastic cell; novel; pre-clinical; safety study; translational clinical trial; tumor; vector

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths in the world with over 1 million cases annually and a median survival time of only 7.8 months in untreated patients. Conditionally replicating viruses targeted to tumors are being developed as a novel class of oncolytic agents for cancer treatment. Vesicular Stomatitis Virus (VSV) is a RNA virus with inherent specificity for replication in tumor cells due to their substantially attenuated anti-viral responses. We demonstrated robust VSV replication and cytopathic effects in cultured rat and human HCC cells, while normal rat and human hepatocytes were completely refractory. We have also constructed a recombinant VSV that expresses a genetically modified fusogenic membrane glycoprotein of the Newcastle disease virus (rVSV-F) and showed that through hepatic artery infusion, it infected and replicated extensively in multi-focal HCC lesions pre-established in the livers of syngeneic and immune-competent rats. The treatment resulted in massive tumor destruction and substantial survival prolongation, and without liver pathology, in the animals. To clinically translate these exciting proof-of-principle laboratory findings, we propose to perform a series of preclinical pharmacological and toxicological studies to assess the safety of rVSV-F in support of an IND to conduct a Phase I clinical translational trial in advanced HCC patients, which will include VSV replication in normal human cells in vitro and assessment of acute toxicity in tumor-bearing rats. Long-term toxicity will be assessed in normal rats and rhesus monkeys. We will also produce, purify, and fully characterize a clinical lot of rVSV-F under cGMP for use in the Phase I dose escalation trial in HCC patients, who will be limited initially to those with Child-Pugh A liver functions and without viral hepatitis. Finally, we will determine the effect of VSV on HCC lesions and surrounding liver tissues in surgically resected specimens from HCC patients of various etiologies including viral hepatitis. The respective tissue slices will be examined for cytopathic effects as well as replication of VSV and the hepatitis viruses in tumor versus liver cells, and the results will be used in considering the expansion of trial subjects to include those with certain underlying liver diseases. The successful conduct of the proposed clinical translational research may lead to the development of recombinant VSV vectors as a novel class of effective and safe oncolytic agents to treat patients with advanced HCC and other cancers in the future.

描述（由申请人提供）：肝细胞癌（HCC）是世界上癌症死亡的第三大主要原因，每年超过100万例，未经治疗的患者的中位生存时间仅为7.8个月。有条件地复制针对肿瘤的病毒正在作为一种新型的用于癌症治疗的癌性药物。囊泡口腔炎病毒（VSV）是一种RNA病毒，由于其大幅减弱的抗病毒反应，具有固有的特异性，可在肿瘤细胞中复制。我们证明了在培养的大鼠和人类HCC细胞中具有强大的VSV复制和细胞病变作用，而正常大鼠和人类肝细胞完全难治性。 We have also constructed a recombinant VSV that expresses a genetically modified fusogenic membrane glycoprotein of the Newcastle disease virus (rVSV-F) and showed that through hepatic artery infusion, it infected and replicated extensively in multi-focal HCC lesions pre-established in the livers of syngeneic and immune-competent rats.该治疗导致动物中大规模的肿瘤破坏和实质性的生存延长，没有肝脏病理。为了在临床上翻译这些令人兴奋的原则实验室发现，我们建议进行一系列临床前药理和毒理学研究，以评估RVSV-F的安全性，以支持IND，以支持高级HCC患者进行I期临床翻译试验，其中将在正常人类细胞中的VSV复制和急性毒性在tumor-bearter-berearter of Tumor-bearter tumor-bearter rats中的毒性。长期毒性将在正常的大鼠和恒河猴中评估。我们还将在CGMP下生产，净化和充分表征临床上的RVSV-F，以在HCC患者的I期剂量升级试验中使用，HCC患者最初将限制为患有儿童肝功能的患者，而没有病毒性肝炎。最后，我们将确定VSV对来自各种病因（包括病毒肝炎）的HCC患者的外科手术切除的标本中HCC病变和周围肝组织的影响。将检查各自的组织切片，以了解肿瘤与肝细胞中VSV和VSV的复制和肝炎病毒的复制，结果将用于考虑试验受试者的扩展，以包括患有某些潜在肝病的人。提出的临床翻译研究的成功进行可能导致重组VSV载体的发展，这是一类新型有效和安全的溶瘤剂，以治疗未来患有高级HCC和其他癌症的患者。