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: 7929907
• 负责人: Savio L Woo
• 金额: $ 48.84万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929907
• 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）是世界上第三大癌症死亡原因，每年有超过 100 万例病例，未经治疗的患者中位生存时间仅为 7.8 个月。针对肿瘤的条件复制病毒正在被开发为一类用于癌症治疗的新型溶瘤剂。水泡性口炎病毒 (VSV) 是一种 RNA 病毒，由于其抗病毒反应大大减弱，因此在肿瘤细胞中具有固有的复制特异性。我们在培养的大鼠和人 HCC 细胞中证明了强大的 VSV 复制和细胞病变效应，而正常大鼠和人肝细胞则完全难以抵抗。我们还构建了表达新城疫病毒基因修饰融合膜糖蛋白（rVSV-F）的重组VSV，并表明通过肝动脉输注，它可以在肝脏中预先建立的多灶性HCC病变中广泛感染和复制同基因和免疫功能正常的大鼠。该治疗导致动物的肿瘤大量破坏并显着延长了生存期，并且没有出现肝脏病变。为了将这些令人兴奋的原理验证实验室研究结果转化为临床，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 HCC 患者中进行 I 期临床转化试验，其中包括 VSV 在正常人类细胞中的体外复制以及对荷瘤大鼠的急性毒性评估。将在正常大鼠和恒河猴中评估长期毒性。我们还将根据 cGMP 生产、纯化和全面表征临床批次的 rVSV-F，用于 HCC 患者的 I 期剂量递增试验，这些患者最初将仅限于具有 Child-Pugh A 肝功能且无病毒性肝炎的患者。最后，我们将确定 VSV 对来自各种病因（包括病毒性肝炎）的 HCC 患者手术切除标本中的 HCC 病变和周围肝组织的影响。将检查相应的组织切片的细胞病变效应以及肿瘤细胞和肝细胞中 VSV 和肝炎病毒的复制，结果将用于考虑扩大试验受试者以包括患有某些潜在肝病的受试者。拟议的临床转化研究的成功进行可能会导致重组 VSV 载体的开发，作为一类新型有效且安全的溶瘤剂，用于未来治疗晚期 HCC 和其他癌症患者。

项目成果

Current good manufacturing practice production of an oncolytic recombinant vesicular stomatitis viral vector for cancer treatment.

用于癌症治疗的溶瘤重组水泡性口炎病毒载体的当前良好生产规范生产。

• DOI: 10.1089/hum.2010.159
• 发表时间: 2011-03-08
• 期刊: Human gene therapy
• 影响因子: 4.2
• 作者: L. Ausubel;M. Meseck;I. Derecho;P. López;C. Knoblauch;R. McMahon;J. Anderson;N. Dunphy;V. Quezada;R. Khan;P. Huang;W. Dang;M. Luo;D. Hsu;S. Woo;L. Couture
• 通讯作者: L. Couture