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Clin Cancer Res. 2010 Mar 1;16(5):1498-508. doi: 10.1158/1078-0432.CCR-09-2804. Epub 2010 Feb 16.

Preclinical investigation of PEGylated tumor necrosis factor alpha in dogs with spontaneous tumors: phase I evaluation.

Author information

  • 1Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, USA. dthamm@colostate.edu

Abstract

PURPOSE:

Tumor necrosis factor-alpha (TNF) is a cytokine with potent antitumor activity; however, toxicity and short half-life have limited its utility. Polyethylene glycol (PEG) conjugation of biotherapeutics can decrease immunogenicity while improving bioactivity and half-life. PEGylation of TNF (PEG-TNF) significantly improved half-life and toxicity in mice, resulting in enhanced antitumor activity. This study characterized toxicity, biological effect, and antitumor activity of PEG-TNF in pet dogs with spontaneous cancer.

EXPERIMENTAL DESIGN:

A phase I clinical trial enrolled dogs with measurable tumors in which standard therapy had failed or been declined. Physiologic, hematologic, and biochemical parameters were evaluated and tumor biopsies obtained serially. A subset of patients underwent serial dynamic contrast-enhanced magnetic resonance imaging.

RESULTS:

Fifteen dogs were enrolled at doses from 20.0 to 30.0 microg/kg. Dose-limiting toxicity at 30.0 microg/kg consisted of vascular leak in one and hypotension/coagulopathy in one, establishing 26.7 microg/kg as the maximum tolerated dose. Mean elimination half-life was 15.3 +/- 4.9 hours. Biological activity (transient fever and leukopenia, increased tumor inflammation, and necrosis) was observed at all dosages. A significant increase in tumor blood flow was observed with dynamic contrast-enhanced magnetic resonance imaging. Minor/transient antitumor responses were observed in dogs with melanoma, squamous cell carcinoma, and mammary carcinoma, and a partial response was observed in a dog with angiosarcoma.

CONCLUSIONS:

Using a clinically relevant, spontaneous large animal model of neoplasia, we have shown that biologically effective doses of PEG-TNF can be administered safely, and that PEG-TNF administration is associated with encouraging biological activity. These results justify the clinical evaluation of PEG-TNF in human cancer.

PMID:
20160058
[PubMed - indexed for MEDLINE]
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