title: Attenuated and protease-profile modified sendai virus vectors as a new tool for virotherapy of solid tumors.
abstract: Multiple types of oncolytic viruses are currently under investigation in clinical trials. To optimize therapeutic outcomes it is believed that the plethora of different tumor types will require a diversity of different virus types. Sendai virus (SeV), a murine parainfluenza virus, displays a broad host range, enters cells within minutes and already has been applied safely as a gene transfer vector in gene therapy patients. However, SeV spreading naturally is abrogated in human cells due to a lack of virus activating proteases. To enable oncolytic applications of SeV we here engineered a set of novel recombinant vectors by a two-step approach: (i) introduction of an ubiquitously recognized cleavage-motive into SeV fusion protein now enabling continuous spreading in human tissues, and (ii) profound attenuation of these rSeV by the knockout of viral immune modulating accessory proteins. When employing human hepatoma cell lines, newly generated SeV variants now reached high titers and induced a profound tumor cell lysis. In contrast, virus release from untransformed human fibroblasts or primary human hepatocytes was found to be reduced by about three log steps in a time course experiment which enables the cumulation of kinetic differences of the distinct phases of viral replication such as primary target cell infection, target cell replication, and progeny virus particle release. In a hepatoma xenograft animal model we found a tumor-specific spreading of our novel recombinant SeV vectors without evidence of biodistribution into non-malignant tissues. In conclusion, we successfully developed novel tumor-selective oncolytic rSeV vectors, constituting a new tool for virotherapy of solid tumors being ready for further preclinical and clinical development to address distinct tumor types.
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: University Childrens Hospital, Tübingen, Germany.
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Bossow
authors.affiliation: Institute for Molecular Medicine Finland FIMM, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Lampe
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Smirnow
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schenk
authors.affiliation: Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, München, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lange
authors.affiliation: Center for Liver Cell Research, Department of Pediatrics and Adolescent Medicine, University of Regensburg Hospital, Regensburg, Germany.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.affiliation: Max-Planck-Institute for Biochemistry, Department Molecular Virology, Martinsried Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Neubert
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Lauer
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bitzer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival; D002522:Chlorocebus aethiops; D005822:Genetic Vectors; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000201:enzymology / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D010447:Peptide Hydrolases / Q000378:metabolism; D015202:Protein Engineering; D059748:Proteolysis; D029082:Sendai virus / Q000235:genetics* / Q000502:physiology; D014709:Vero Cells; D019562:Viral Load; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
chemical_list: D009363:Neoplasm Proteins; D014764:Viral Proteins; D010447:Peptide Hydrolases