Systemic vector leakage and transgene expression by intratumorally injected recombinant adenovirus vectors.
Interleukin 12 is a heterodimeric cytokine that exhibits potent immunostimulatory effects. It has shown some promise in preclinical and clinical studies but was accompanied by serious systemic toxicity such as flu-like syndromes, a rapid transient leukopenia, elevated liver transaminases, gastrointestinal toxicity, and/or liver dysfunction. Gene therapy with intratumorally injected recombinant adenoviral vectors offers the potential to restrict therapeutic gene expression in the tumor. Here we show that a substantial amount of adenoviral vectors disseminates into the systemic circulation and infects parenchymal organs. We further show that this results in high systemic levels of potentially toxic transgene products. To reduce potential toxicity, we tested an inducible promoter based on the heat shock proteins (hsp70B) and present evidence that high intratumoral levels of a therapeutic transgene can be obtained while systemic expression is reduced to a minimum, increasing the safety of adenovirus-based tumor gene therapy.
Lohr
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Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Huang
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Hu
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Dewhirst
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MW
Li
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D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004274:DNA, Recombinant / Q000235:genetics; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006358:Hot Temperature; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013154:Spleen / Q000378:metabolism; D019076:Transgenes / Q000235:genetics*; D014407:Tumor Cells, Cultured
D004274:DNA, Recombinant; D018840:HSP70 Heat-Shock Proteins; D018664:Interleukin-12