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，未经治疗的患者中位生存期仅为7.8个月。靶向肿瘤的有条件复制病毒作为一类新的肿瘤治疗溶瘤剂正在被开发。水疱性口炎病毒（VSV）是一种RNA病毒，由于其抗病毒反应明显减弱，因此具有在肿瘤细胞中复制的固有特异性。我们证明VSV在培养的大鼠和人HCC细胞中具有强大的复制和细胞病变作用，而正常大鼠和人肝细胞则完全难治。我们还构建了一种表达新城疫病毒（rVSV-F）基因修饰的融合原膜糖蛋白的重组VSV，并表明通过肝动脉输注，它可以在同基因和免疫能力强的大鼠肝脏中预先建立的多灶性HCC病变中广泛感染和复制。在动物中，这种治疗导致了大量的肿瘤破坏和大量的生存延长，并且没有肝脏病理。为了临床转化这些令人兴奋的原理证明实验室发现，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，其中将包括体外正常人类细胞中的VSV复制和评估荷瘤大鼠的急性毒性。将对正常大鼠和恒河猴进行长期毒性评估。我们还将在cGMP下生产、纯化和充分表征一批临床批次的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，我们将在包括病毒性肝炎在内的各种病因的HCC患者手术切除标本中确定VSV对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VSV和肝炎病毒在肿瘤与肝细胞中的复制情况，结果将用于考虑扩大试验对象，包括那些患有某些潜在肝脏疾病的人。该临床转化研究的成功进行，可能会导致重组VSV载体的发展，成为未来治疗晚期HCC和其他癌症患者有效安全的新型溶瘤药物。

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.