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: 7276134
• 负责人: Savio L Woo
• 金额: $ 59.22万
• 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/7276134
• 关键词: Acute; Animals; Antiviral Response; Attenuated; Cancer Etiology; Cells; Cessation of life; Child; Class; 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; Production; 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; cancer therapy; concept; liver function; neoplastic cell; novel; pre-clinical; 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(申请人提供)：肝细胞癌(HCC)是世界上第三大癌症死亡原因，每年超过100万例，未经治疗的患者的中位生存期仅为7.8个月。针对肿瘤的有条件复制病毒正被开发为一类用于癌症治疗的新型溶瘤药物。水泡性口炎病毒(VSV)是一种具有固有特异性的RNA病毒，由于其抗病毒反应显著减弱，因此可在肿瘤细胞中复制。我们在培养的大鼠和人肝癌细胞中显示了强大的VSV复制和细胞病变效应，而正常大鼠和人肝细胞是完全难治的。我们还构建了表达基因修饰的新城疫病毒融合膜糖蛋白(rVSV-F)的重组VSV，并表明它通过肝动脉灌注，在同基因和免疫活性大鼠肝脏中预先建立的多灶性肝癌病变中广泛感染和复制。这种治疗在动物体内导致了大量的肿瘤破坏和大量的生存时间延长，并且没有肝脏病理。为了将这些令人兴奋的原则验证实验室结果转化为临床，我们建议进行一系列临床前药理学和毒理学研究，以评估rVSV-F的安全性，以支持IND在晚期肝癌患者中进行I期临床翻译试验，其中将包括VSV在体外正常人类细胞中的复制和对荷瘤大鼠的急性毒性评估。长期毒性将在正常大鼠和恒河猴身上进行评估。我们还将在cGMP下生产、纯化和充分鉴定临床上大量的rVSV-F，用于肝细胞癌患者的I期剂量递增试验，最初仅限于肝功能为Child-Pugh A且没有病毒性肝炎的患者。最后，我们将在包括病毒性肝炎在内的各种原因的肝细胞癌患者的手术切除标本中，确定VSV对肝细胞癌病变和周围肝组织的影响。相关的组织切片将被检查细胞病变效应以及VSV和肝炎病毒在肿瘤和肝细胞中的复制，结果将被用于考虑扩大试验对象，将那些患有某些潜在肝病的人包括在内。这项临床转化研究的成功可能导致重组VSV载体作为一类新型的有效和安全的溶瘤药物在未来用于治疗晚期肝癌和其他癌症患者。