Geletneky Karsten, Leoni Anne-Laure, Pohlmeyer-Esch Gabriele, Loebhard Stephanie, Baetz Andrea, Leuchs Barbara, Roscher Mandy, Hoefer Constance, Jochims Karin, Dahm Michael, Huber Bernard, Rommelaere Jean, Krebs Ottheinz, Hajda Jacek
Department of Neurosurgery, University Hospital, Heidelberg, Germany; Department of Applied Tumor Virology, German Cancer Research Center, Heidelberg, Germany.
BSL BIOSERVICE Scientific Laboratories GmbH, Planegg, Munich, Germany.
Comp Med. 2015 Feb;65(1):23-35.
Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated.
细小病毒H1（H1PV）是一种在啮齿动物群体中传播的自主细小病毒。它的天然宿主是大鼠。H1PV感染通常无致病性，除非在大鼠和仓鼠的胎儿及新生儿中。在临床前模型中，H1PV感染人类癌细胞会产生强烈的溶瘤作用。为了进行针对脑肿瘤患者的H1PV临床试验，按照药品生产质量管理规范生产了临床级别的H1PV。本报告重点关注在30只大鼠中单次高剂量静脉注射高纯度H1PV以及在223只大鼠中以3个剂量水平进行多次（n = 17）静脉注射后获得的结果。在这两项研究中，均未发生与病毒相关的死亡或与H1PV相关的宏观器官变化。多次病毒注射后的组织病理学检查显示，最高剂量组动物的肝脏出现轻微的弥漫性胆管增生，高剂量组动物的脾脏出现生发中心发育。肝脏变化在最后一次注射后的2周恢复期内可逆转。血液学、血液化学和凝血分析未显示出因H1PV导致的显著毒理学变化。病毒注射刺激了IgG抗体的产生，但未改变单核细胞功能或诱导细胞因子释放。PCR分析显示，在所有测试器官中病毒基因组水平呈剂量依赖性。病毒主要通过粪便排出。这些数据提供了有关H1PV在其天然宿主中感染的重要信息。由于在允许的动物模型中证实了H1PV具有良好的安全性，因此可以启动针对脑肿瘤患者的H1PV I/IIa期临床试验。
