Effects of capsid-modified oncolytic adenoviruses and their combinations with gemcitabine or silica gel on pancreatic cancer

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...

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Bibliographic Details
Published in:	International journal of cancer Vol. 131; no. 1; pp. 253 - 263
Main Authors:	Kangasniemi, Lotta, Parviainen, Suvi, Pisto, Tommi, Koskinen, Mika, Jokinen, Mika, Kiviluoto, Tuula, Cerullo, Vincenzo, Jalonen, Harry, Koski, Anniina, Kangasniemi, Anna, Kanerva, Anna, Pesonen, Sari, Hemminki, Akseli
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-07-2012 Wiley-Blackwell Wiley Subscription Services, Inc
Subjects:	Adenoviruses Adenoviruses, Human - genetics Adenoviruses, Human - immunology Animals Antibodies Antibodies, Neutralizing Biological and medical sciences Cancer Cancer therapies Capsid - chemistry Capsid Proteins - genetics Capsid Proteins - metabolism Cell Line, Tumor Chemotherapy Clinical trials Combined Modality Therapy Cricetinae Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology Deoxycytidine - therapeutic use Female Gastroenterology. Liver. Pancreas. Abdomen Gemcitabine Gene therapy Gene transfer Humans Immune response Liver cancer Liver. Biliary tract. Portal circulation. Exocrine pancreas Medical research Medical sciences Mice Oncolysis Oncolytic Virotherapy - methods oncolytic virus Oncolytic Viruses - genetics Oncolytic Viruses - immunology Pancreas Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - immunology Pancreatic Neoplasms - therapy Silica Gel Transfection Transplants & implants Tumor cell lines Tumors Antineoplastic agent Adenoviridae Gemcitabine Malignant tumor Oncolytic virus Silica Virus pancreatic cancer Cancerology Treatment Antimetabolic Pancreas cancer Pyrimidine derivatives Digestive diseases Fluorine Organic compounds Capsid Gene therapy Pyrimidine nucleoside Cancer Pancreatic disease
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Summary:	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.
Bibliography:	Finnish Society of Gastroenterology Finnish Cultural Foundation Conflict of interest: A.H. is shareholder in Oncos Therapeutics Ltd. HUCH and TUCH Research Funds (EVO) University of Helsinki Otto A. Malm Foundation Oskar Öflund Foundation Sigrid Juselius Foundation Finnish Cancer Society Bayer-Shering Pharma Research Foundation Academy of Finland Biocentrum Helsinki and Biocenter Finland European Research Council American Society of Clinical Oncology Foundation for the Finnish Cancer Institute EU FP6 APOTHERAPY and THERADPOX ArticleID:IJC26370 ark:/67375/WNG-3RL1P521-2 K. Albin Johansson Foundation istex:C7FCD30CF2CDFCC07FA0C8927999432FDF7C3122 Finnish-Norwegian Medical Foundation Orion-Farmos Research Foundation Fax: +358‐9‐191‐25610 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0020-7136 1097-0215
DOI:	10.1002/ijc.26370