Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for prostate cancer

Molecular Therapy Oncolytics
Svend O FreytagFarzan Siddiqui

Abstract

The purpose of this study was to examine the toxicity of combining oncolytic adenovirus-mediated cytotoxic and interleukin 12 (IL-12) gene therapy in a preclinical model to support future phase 1 trials. One hundred and twenty C57BL/6 male mice received an intraprostatic injection of saline (n = 24) or an oncolytic adenovirus (Ad5-yCD/mutTKSR39rep-mIL12) expressing two suicide genes and mouse IL-12 (n = 96). The adenovirus was administered at three dose levels (1.3 × 10(6), 1.3 × 10(7), 1.3 × 10(8) vp/kg) followed by 2 weeks of 5-flurocytosine (5-FC) and gancliclovir (GCV) prodrug therapy. There were no premature deaths. Daily observations of animals did not reveal any obvious clinical problems throughout the 78-day in-life phase of the study. Animals in the highest adenovirus dose group exhibited lymphopenia and transaminitis on day 3, both of which resolved by day 17. Except for mild inflammation of the prostate and seminal vesicles, histopathology of major organs was largely unremarkable. IL-12 and interferon-gamma levels in prostate and serum peaked on day 3 and were either undetectable or returned to baseline levels by day 17. No adenoviral DNA was detected in serum in any group at any time point. The results demonstrate t...Continue Reading

References

Jan 10, 2002·Human Gene Therapy·Michael A SchnellJames M Wilson
Mar 20, 2002·Cytokine & Growth Factor Reviews·Mario P Colombo, Giorgio Trinchieri
Feb 4, 2003·Nature Reviews. Immunology·Giorgio Trinchieri
Apr 16, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Bruno SangroJesus Prieto
Apr 23, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Carla M van HerpenPieter H de Mulder
Jan 18, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Svend O FreytagJae Ho Kim
Mar 22, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Svend O FreytagJae Ho Kim
Apr 5, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Svend O FreytagJae Ho Kim
Aug 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michele Del VecchioAndrea Anichini
Aug 21, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kenneth N BartonBenjamin Movsas
May 19, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kenneth N BartonSvend O Freytag
Jul 12, 2012·Nature Biotechnology·Stephen J RussellJohn C Bell

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Citations

Jul 6, 2016·Current Opinion in Virology·Amanda Rosewell Shaw, Masataka Suzuki
Aug 6, 2016·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Brian A Keller, John C Bell
Mar 13, 2019·Human Gene Therapy. Clinical Development·Robert Allen KaiserJoseph Benjamin Lillegard
Jul 3, 2018·Oncology Letters·Tinglu LiHe Huang
Aug 15, 2019·Therapeutic Innovation & Regulatory Science·Paul Baldrick
May 28, 2020·Cancers·Mizuho Sato-DahlmanMasato Yamamoto
Nov 13, 2020·Frontiers in Immunology·Khue G NguyenDavid A Zaharoff
Feb 28, 2021·Nature Reviews. Urology·Justin R Gregg, Timothy C Thompson
Aug 30, 2020·Cytokine & Growth Factor Reviews·Evelyne TassoneJohn Hiscott
Jul 29, 2021·NAR Cancer·Estela Núñez-ManchónCristina Fillat

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Methods Mentioned

BETA
PCR
enzyme-linked immunosorbent assay
ELISA

Software Mentioned

SigmaPlot

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