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


METHODS
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.
Thamm
Douglas H
DH
Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, USA. dthamm@colostate.edu
Kurzman
Ilene D
ID
Clark
Mike A
MA
Ehrhart
E J
EJ
Kraft
Susan L
SL
Gustafson
Daniel L
DL
Vail
David M
DM
D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000662:veterinary*; D011092:Polyethylene Glycols; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols