Regulated intratumoral expression of IL-12 using a RheoSwitch Therapeutic System® (RTS® ) gene switch as gene therapy for the treatment of glioma

Cancer Gene Therapy
John A BarrettFrancois Lebel

Abstract

The purpose of this study was to determine if localized delivery of IL-12 encoded by a replication-incompetent adenoviral vector engineered to express IL-12 via a RheoSwitch Therapeutic System® (RTS®) gene switch (Ad-RTS-IL-12) administered intratumorally which is inducibly controlled by the oral activator veledimex is an effective approach for glioma therapy. Mice bearing 5-10-day-old intracranial GL-261 gliomas were intratumorally administered Ad-RTS-mIL-12 in which IL-12 protein expression is tightly controlled by the activator ligand, veledimex. Local tumor viral vector levels concomitant with veledimex levels, IL-12-mRNA expression, local and systemic cytokine expression, tumor and systemic flow cytometry and overall survival were studied. Ad-RTS-mIL-12+veledimex elicited a dose-related increase in tumor IL-12 mRNA and IL-12 protein and discontinuation of veledimex resulted in a return to baseline levels. These changes correlated with local immune and antitumor responses. Veledimex crossed the blood-brain barrier in both orthotopic GL-261 mice and cynomolgus monkeys. We have demonstrated that this therapy induced localized controlled production of IL-12 which correlates with an increase in tumor-infiltrating lymphocytes (T...Continue Reading

References

Jan 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·J TrentB Vogelstein
May 9, 1998·Neurosurgery·W C JeanW C Low
Mar 4, 2000·Journal of Neurosurgery·F DiMecoA Olivi
Jul 6, 2000·Laboratory Investigation; a Journal of Technical Methods and Pathology·D ZagzagM Grumet
Mar 13, 2003·European Journal of Biochemistry·Subba R PalliDean E Cress
Dec 16, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Guillermo MazzoliniIgnacio Melero
Feb 7, 2006·Current Gene Therapy·Bruno SangroJesus Prieto
Aug 4, 2006·Journal of Leukocyte Biology·Jana GoldmannIngo Bechmann
Jul 10, 2007·Acta Neuropathologica·David N LouisPaul Kleihues
Aug 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michele Del VecchioAndrea Anichini
Aug 30, 2008·International Journal of Cancer. Journal International Du Cancer·Carla M L van HerpenPieter H M De Mulder
Dec 2, 2008·Journal of Neuro-oncology·Andrew D NordenPatrick Y Wen
Dec 30, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Xi ZhaoWalter J Storkus
May 4, 2013·The Lancet Oncology·Bodo E Lippitz
Jun 4, 2013·The New England Journal of Medicine·Jedd D WolchokMario Sznol
Nov 21, 2013·Journal of Cellular and Molecular Medicine·Louis Z WeiChristopher J Paige
Nov 28, 2013·The Journal of Experimental Medicine·Johannes Vom BergBurkhard Becher
Jun 24, 2014·Cancer Control : Journal of the Moffitt Cancer Center·Dawn E Dolan, Shilpa Gupta
Nov 8, 2015·Cancer Immunology Research·David A ReardonGordon J Freeman
May 14, 2016·Clinical Oncology : a Journal of the Royal College of Radiologists·T CarterP Mulholland
Jul 28, 2016·JCI Insight·Joseph P AntoniosRobert M Prins
Dec 29, 2016·The New England Journal of Medicine·Christine E BrownBehnam Badie
Apr 2, 2017·The Breast : Official Journal of the European Society of Mastology·Giancarlo PruneriCarsten Denkert
Apr 4, 2017·The American Journal of Surgical Pathology·Gerald SaldanhaMark Bamford

❮ Previous
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Citations

Oct 17, 2018·Future Oncology·Premal H ThakerKhursheed Anwer
Jul 12, 2019·Nature Reviews. Drug Discovery·Kevin HarringtonJean-Charles Soria
May 13, 2020·Expert Opinion on Therapeutic Targets·Matthew MuirGanesh Rao
May 14, 2020·Expert Opinion on Investigational Drugs·Maria B Garcia-FabianiMaria G Castro
Mar 12, 2020·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Ami PatelDavid B Weiner
May 28, 2020·Cancers·Mizuho Sato-DahlmanMasato Yamamoto
Oct 6, 2020·Frontiers in Immunology·María Tristán-ManzanoFrancisco Martin
Jan 10, 2019·Cancer Gene Therapy·Guillermo GarauletAntonio Rodríguez
Feb 23, 2019·Current Treatment Options in Oncology·Tresa McGranahanSeema Nagpal
Aug 31, 2020·Critical Reviews in Biotechnology·Aarti DoshiPatrick C Cirino
Aug 16, 2019·Science Translational Medicine·E Antonio ChioccaLaurence J N Cooper
Aug 10, 2019·Frontiers in Immunology·Andy S DingMichael Lim
Oct 18, 2020·International Journal of Molecular Sciences·Sergio Rius-RocabertEstanislao Nistal-Villan
Aug 21, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Susannah L HewittNadia Luheshi
Dec 17, 2020·Cancers·Oleg MozheiSergey Kasparov
Nov 13, 2020·Frontiers in Immunology·Khue G NguyenDavid A Zaharoff
Apr 2, 2021·Frontiers in Molecular Neuroscience·Kaushik BanerjeeMaria G Castro
Apr 10, 2021·Nature Reviews. Drug Discovery·Cedrik M BrittenAxel Hoos
Apr 29, 2021·Nature Reviews. Cancer·Mansi SaxenaNina Bhardwaj
Jul 16, 2020·Current Drug Metabolism·Elmira MohtashamiAmir R Afshari
Aug 6, 2021·Human Gene Therapy·Grace Elizabeth MuliaMarxa Leão Figueiredo
Aug 10, 2021·Frontiers in Microbiology·Yaqi ZhaoBin Xu
Aug 14, 2020·ACS Combinatorial Science·Priscilla DoErik C Dreaden
Feb 2, 2021·Neurosurgical Focus·Alexander F HaddadManish K Aghi

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Methods Mentioned

BETA
PCR
reverse transcription PCR
enzyme-linked immunosorbent assay
ELISA
flow cytometry

Clinical Trials Mentioned

NCT01397708
NCT02026271

Software Mentioned

GraphPad
WinNonlin
BD [UNK]
GraphPrism
Phoenix

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