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

Gene Therapy volume 8, pages 259–267 (2001)Cite this article

Abstract

Despite the efficacy of IL-12 in cancer experimental models, clinical trials with systemic recombinant IL-12 showed unacceptable toxicity related to endogenous IFNγ 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 × 109 p.f.u., systemic AdCMVmIL-12 killed all C57BL/6 mice but spared all BALB/c mice. Much higher IFNγ 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 IFNγ inducer. Interestingly, lethal toxicity in C57BL/6 mice was abolished by administration of blocking anti-IFNγ mAbs and also by simultaneous depletion of T cells, NK cells, and macrophages. These observations together with the great dispersion of IFNγ produced by human PBMCs upon in vitro stimulation with IL-12, or infection with recombinant adenovirus encoding IL-12, suggest that patients might also show heterogeneous degrees of toxicity in response to IL-12 gene transfer.

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Acknowledgements

We thank our colleagues Dr Bustos, Dr Novo and Dr Lasarte for their suggestions and critical reading. Technical assistance by Izaskun Gabari, Celia Gomar and Elena Villanueva is also acknowledged. Financial support was from CICYT (SAF98–0146, SAF99–0039 and SAF99–0084) and generous grants from Fundación Ramón Areces and Inés Bemberg.

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  1. I Melero and C Quian: The last two authors will equally share credit for senior authorship

Authors and Affiliations

  1. Department of Internal Medicine, Gene Therapy Unit, School of Medicine, University of Navarra, Irunlarrea, 1 (31080), Pamplona, Spain

    G Mazzolini, I Narvaiza, A Pérez-Diez, M Rodriguez-Calvillo, C Qian, B Sangro, J Ruiz, J Prieto, I Melero & C Quian

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  1. G Mazzolini
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  2. I Narvaiza
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Mazzolini, G., Narvaiza, I., Pérez-Diez, A. et al. Genetic heterogeneity in the toxicity to systemic adenoviral gene transfer of interleukin-12. Gene Ther 8, 259–267 (2001). https://doi.org/10.1038/sj.gt.3301387

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