title: Immunogenic Human Papillomavirus Pseudovirus-Mediated Suicide-Gene Therapy for Bladder Cancer.
abstract: Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral resection of the lesion. However, this treatment is associated with significant side-effects and treatment failures, highlighting the necessity of novel strategies. One potent approach is the suicide-gene mediated therapy/prodrug combination, provided tumor-specificity can be ensured and anti-tumor immune responses induced. Using the mouse syngeneic orthotopic MB49-bladder tumor model, here we show that IVES human papillomavirus non-replicative pseudovirions (PsV) can pseudoinfect tumors with a ten-fold higher efficacy than normal bladders. In addition, PsV carrying the suicide-gene herpes-simplex virus thymidine kinase (PsV-TK) combined to Ganciclovir (GCV) led to immunogenic cell-death of tumor cells in vitro and to MB49-specific CD8 T-cells in vivo. This was associated with reduction in bladder-tumor growth and increased mice survival. Altogether, our data show that IVES PsV-TK/GCV may be a promising alternative or combinatory treatment for NMIBC.
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1011, Switzerland. reem.hojeij@gmail.com.
authors.forename: Rim
authors.initials: R
authors.lastname: Hojeij
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1011, Switzerland. Sonia.domingos-pereira@chuv.ch.
authors.forename: Sonia
authors.initials: S
authors.lastname: Domingos-Pereira
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1011, Switzerland. marianne.nkosi@epfl.ch.
authors.forename: Marianne
authors.initials: M
authors.lastname: Nkosi
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1011, Switzerland. dalilagh8@gmail.com.
authors.forename: Dalila
authors.initials: D
authors.lastname: Gharbi
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1011, Switzerland. laurent.derre@chuv.ch.
authors.forename: Laurent
authors.initials: L
authors.lastname: Derré
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. schillej@dc37a.nci.nih.gov.
authors.forename: John T
authors.initials: JT
authors.lastname: Schiller
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1011, Switzerland. patrice.jichlinski@chuv.ch.
authors.forename: Patrice
authors.initials: P
authors.lastname: Jichlinski
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne 1011, Switzerland. dnardell@hospvd.ch.
authors.forename: Denise
authors.initials: D
authors.lastname: Nardelli-Haefliger
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003131:Combined Modality Therapy; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D027383:Papillomaviridae / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*
chemical_list: D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir
keywords: bladder cancer; human papillomavirus vectors; immunogenic suicide-gene therapy; tumor-targeting