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

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。靶向肿瘤的连续复制病毒正在被开发为一类新型的用于癌症治疗的溶瘤剂。水泡性口炎病毒（VSV）是一种RNA病毒，由于其基本上减弱的抗病毒反应，对肿瘤细胞中的复制具有固有特异性。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是完全难治的。我们还构建了一个重组VSV，表达基因修饰的融合膜糖蛋白的纽卡斯尔病病毒（rVSV-F），并表明，通过肝动脉输注，它感染和复制广泛的多灶性肝癌病变预先建立在同基因和免疫功能正常的大鼠的肝脏。该治疗导致动物的大规模肿瘤破坏和显著的生存期延长，并且没有肝脏病理学。为了临床转化这些令人兴奋的原理验证实验室发现，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，其中包括体外正常人细胞中的VSV复制和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、纯化和充分表征rVSV-F的临床批次，用于HCC患者的I期剂量递增试验，这些患者最初将限于Child-Pugh A肝功能和无病毒性肝炎的患者。最后，我们将确定VSV对各种病因包括病毒性肝炎的HCC患者手术切除标本中HCC病变和周围肝组织的影响。将检查相应组织切片的细胞病变效应以及VSV和肝炎病毒在肿瘤与肝细胞中的复制，并将使用结果考虑扩大试验受试者，以纳入患有某些基础肝病的受试者。拟议的临床转化研究的成功进行可能会导致重组VSV载体的发展，作为一种新型的有效和安全的溶瘤药物，以治疗晚期肝癌和其他癌症患者的未来。

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.