title: Deletion ofF4L(ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti-tumor immunity with superior safety in bladder cancer models.
abstract: Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high-grade disease, Bacillus Calmette-Guérin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating theF4Lgene that encodes the virus homolog of the cell-cycle-regulated small subunit of ribonucleotide reductase (RRM2). TheF4L-deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor-selective replication and cell killing. TheseF4L-deleted VACVs replicated selectively in immune-competent rat AY-27 and xenografted human RT112-luc orthotopic bladder cancer models, causing significant tumor regression or complete ablation with no toxicity. It was also observed that rats cured of AY-27 tumors by VACV treatment developed anti-tumor immunity as evidenced by tumor rejection upon challenge and byex vivocytotoxic T-lymphocyte assays. Finally,F4L-deleted VACVs replicated in primary human bladder cancer explants. Our findings demonstrate the enhanced safety and selectivity ofF4L-deleted VACVs, with application as a promising therapy for patients with BCG-refractory cancers and immune dysregulation.
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Potts
authors.affiliation: Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Department of Medical Microbiology & Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Irwin
authors.affiliation: Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Department of Medical Microbiology & Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Favis
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Desmond B
authors.initials: DB
authors.lastname: Pink
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Department of Anatomy & Cell Biology, Faculty of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Krista M
authors.initials: KM
authors.lastname: Vincent
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: John D
authors.identifier: 0000-0002-7734-1204
authors.initials: JD
authors.lastname: Lewis
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Moore
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Hitt
authors.affiliation: Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada devans@ualberta.ca.|Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.|Department of Medical Microbiology & Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: David H
authors.identifier: 0000-0001-5871-299X
authors.initials: DH
authors.lastname: Evans
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007109:Immunity; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D051381:Rats; D012264:Ribonucleotide Reductases / Q000235:genetics* / Q000276:immunology; D014407:Tumor Cells, Cultured; D001743:Urinary Bladder / Q000276:immunology / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication
chemical_list: D014764:Viral Proteins; D012264:Ribonucleotide Reductases
keywords: bladder cancer; immunotherapy; oncolytic virus; ribonucleotide reductase; vaccinia virus