Genetic heterogeneity in the toxicity to systemic adenoviral gene transfer of interleukin-12

Gene Therapy
Guillermo MazzoliniIgnacio Melero

Abstract

Despite the efficacy of IL-12 in cancer experimental models, clinical trials with systemic recombinant IL-12 showed unacceptable toxicity related to endogenous IFNgamma production. We report that systemic administration of a recombinant adenovirus encoding IL-12 (AdCMVmIL-12) has a dramatically different survival outcome in a number of mouse pure strains over a wide range of doses. For instance at 2.5 x 10(9) p.f.u., systemic AdCMVmIL-12 killed all C57BL/6 mice but spared all BALB/c mice. Much higher IFNgamma concentrations in serum samples of C57BL/6 than in those from identically treated BALB/c were found. Causes for heterogeneous toxicity can be traced to differences among murine strains in the levels of gene transduction achieved in the liver, as assessed with adenovirus coding for reporter genes. In accordance, IL-12 serum concentrations are higher in susceptible mice. In addition, sera from C57BL/6 mice treated with AdCMVmIL-12 showed higher levels of IL-18, a well-known IFNgamma inducer. Interestingly, lethal toxicity in C57BL/6 mice was abolished by administration of blocking anti-IFNgamma mAbs and also by simultaneous depletion of T cells, NK cells, and macrophages. These observations together with the great dispersion...Continue Reading

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Citations

Dec 14, 2002·The International Journal of Biochemistry & Cell Biology·Bruno SangroJesus Prieto
Feb 23, 2007·Nature Clinical Practice. Endocrinology & Metabolism·Marinella Messina, Bruce G Robinson
Mar 11, 2009·Journal of Biomedical Science·Pablo MatarGuillermo Mazzolini
Aug 29, 2003·BMC Pharmacology·Pierre LefesvreDirk van Bekkum
Apr 14, 2005·European Journal of Gastroenterology & Hepatology·Bruno SangroJesus Prieto
Jul 23, 2004·Expert Opinion on Biological Therapy·Jesus PrietoM Gabriela Kramer
Aug 29, 2012·Journal of Tissue Engineering and Regenerative Medicine·Demissew Shenegelegn MernAldemar Andres Hegewald
May 31, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·Anne KiangAndrea Amalfitano
May 7, 2002·Molecular Therapy : the Journal of the American Society of Gene Therapy·Philipp Mayer-KuckukJoseph R Bertino
Jun 21, 2005·Molecular Therapy : the Journal of the American Society of Gene Therapy·Juan R Rodriguez-MadozCristian Smerdou
Jun 1, 2005·Molecular Therapy : the Journal of the American Society of Gene Therapy·Maria VeraGloria González-Aseguinolaza
Dec 16, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Guillermo MazzoliniIgnacio Melero
Apr 16, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Bruno SangroJesus Prieto
Apr 6, 2004·The Surgical Clinics of North America·Jesus PrietoGuillermo Mazzolini
Jun 19, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Maria Cecilia Rodriguez-GalanHoward A Young
Nov 13, 2020·Frontiers in Immunology·Khue G NguyenDavid A Zaharoff

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