Ottawa Hospital Research Institute, Cancer Therapeutics Program, 501 Smyth Road, Ottawa, Ontario, Canada; University of Ottawa, Faculty of Medicine, 451 Smyth Rd, Ottawa, Ontario, Canada.
German Cancer Research Center (DKFZ), Clinical Cooperation Unit Virotherapy, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany; National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Department of Medical Oncology, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
J Virol Methods. 2022 Apr;302:114487. doi: 10.1016/j.jviromet.2022.114487. Epub 2022 Jan 29.
The use of oncolytic viruses (OV) to precisely target and eliminate tumors ('virotherapy') is a rapidly evolving therapeutic approach to treating cancer. A major obstacle in virotherapy, especially for systemic administration, is the host's immune response towards the OV. In the case of measles virus (MeV), most individuals have been immunized against this agent leading to pre-existing neutralizing antibodies that can impair OV delivery to the tumor. These antibodies predominantly target the hemagglutinin (H) and fusion (F) envelope glycoproteins displayed at the particle's surface. Here, we introduce a novel and versatile pseudotyping platform for rapid envelope exchange of oncolytic MeV that allows for engineering of chimeric viruses invulnerable to pre-existing anti-MeV antibodies. Using this system, we have successfully exchanged the MeV F and H proteins with the glycoprotein G of vesicular stomatitis virus (VSV) and the surface proteins of Newcastle disease virus (NDV) or canine distemper virus (CDV), all of which are not endemic in the general human population. While the MeV-VSV and MeV-NDV pseudotypes were non-functional, the MeV-CDV pseudotype was successfully propagated to high-titer virus stocks. This study describes the successful generation of a robust envelope exchange platform for oncolytic MeV while also highlighting its intricate pseudotyping tolerance.
溶瘤病毒（OV）被用于精确靶向和消除肿瘤（“病毒疗法”），这是一种治疗癌症的快速发展的治疗方法。病毒疗法的一个主要障碍，特别是对于系统给药，是宿主对 OV 的免疫反应。在麻疹病毒（MeV）的情况下，大多数人已经对该药物进行了免疫接种，导致存在预先存在的中和抗体，这可能会损害 OV 向肿瘤的递呈。这些抗体主要针对颗粒表面展示的血凝素（H）和融合（F）包膜糖蛋白。在这里，我们引入了一种用于快速交换溶瘤性 MeV 包膜的新型多功能假型平台，该平台允许对不易受预先存在的抗 MeV 抗体影响的嵌合病毒进行工程设计。使用该系统，我们成功地用水疱性口炎病毒（VSV）的糖蛋白 G 和新城疫病毒（NDV）或犬瘟热病毒（CDV）的表面蛋白交换了 MeV 的 F 和 H 蛋白，所有这些蛋白在普通人群中都不是地方性的。虽然 MeV-VSV 和 MeV-NDV 假型是无功能的，但 MeV-CD 假型成功地繁殖到高滴度病毒株。这项研究描述了成功生成用于溶瘤性 MeV 的稳健包膜交换平台，同时还强调了其复杂的假型耐受性。
