title: Effects of capsid-modified oncolytic adenoviruses and their combinations with gemcitabine or silica gel on pancreatic cancer.
abstract: Conventional cancer treatments often have little impact on the course of advanced pancreatic cancer. Although cancer gene therapy with adenoviruses is a promising developmental approach, the primary receptor is poorly expressed in pancreatic cancers which might compromise efficacy and thus targeting to other receptors could be beneficial. Extended stealth delivery, combination with standard chemotherapy or circumvention of host antiadenoviral immune response might improve efficacy further. In this work, capsid-modified adenoviruses were studied for transduction of cell lines and clinical normal and tumor tissue samples. The respective oncolytic viruses were tested for oncolytic activity in vitro and in vivo. Survival was studied in a peritoneally disseminated pancreas cancer model, with or without concurrent gemcitabine while silica implants were utilized for extended intraperitoneal virus delivery. Immunocompetent mice and Syrian hamsters were used to study the effect of silica mediated delivery on antiviral immune responses and subsequent in vivo gene delivery. Capsid modifications selectively enhanced gene transfer to malignant pancreatic cancer cell lines and clinical samples. The respective oncolytic viruses resulted in increased cell killing in vitro, which translated into a survival benefit in mice. Early proinfammatory cytokine responses and formation of antiviral neutralizing antibodies was partially avoided with silica implants. The implant also shielded the virus from pre-existing neutralizing antibodies, while increasing the pancreas/liver gene delivery ratio six-fold. In conclusion, capsid modified adenoviruses would be useful for testing in pancreatic cancer trials. Silica implants might increase the safety and efficacy of the approach.
authors.affiliation: Cancer Gene Therapy Group, Molecular Cancer Biology Program, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Finland.
authors.forename: Lotta
authors.initials: L
authors.lastname: Kangasniemi
authors.forename: Suvi
authors.initials: S
authors.lastname: Parviainen
authors.forename: Tommi
authors.initials: T
authors.lastname: Pisto
authors.forename: Mika
authors.initials: M
authors.lastname: Koskinen
authors.forename: Mika
authors.initials: M
authors.lastname: Jokinen
authors.forename: Tuula
authors.initials: T
authors.lastname: Kiviluoto
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: Harry
authors.initials: H
authors.lastname: Jalonen
authors.forename: Anniina
authors.initials: A
authors.lastname: Koski
authors.forename: Anna
authors.initials: A
authors.lastname: Kangasniemi
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing; D002213:Capsid / Q000737:chemistry; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D006224:Cricetinae; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D058428:Silica Gel; D014162:Transfection; D000093542:Gemcitabine
chemical_list: D057134:Antibodies, Neutralizing; D036022:Capsid Proteins; D003841:Deoxycytidine; D058428:Silica Gel; D000093542:Gemcitabine