Portions of this material were presented in abstract form to the 31st Annual Conference of the Veterinary Cancer Society, Albuquerque, NM, November 2011.
Clinical and Immunomodulatory Effects of Toceranib Combined with Low-Dose Cyclophosphamide in Dogs with Cancer
Article first published online: 4 FEB 2012
Copyright © 2012 by the American College of Veterinary Internal Medicine
Journal of Veterinary Internal Medicine
Volume 26, Issue 2, pages 355–362, March-April 2012
How to Cite
Mitchell, L., Thamm, D.H. and Biller, B.J. (2012), Clinical and Immunomodulatory Effects of Toceranib Combined with Low-Dose Cyclophosphamide in Dogs with Cancer. Journal of Veterinary Internal Medicine, 26: 355–362. doi: 10.1111/j.1939-1676.2011.00883.x
- Issue published online: 20 MAR 2012
- Article first published online: 4 FEB 2012
- Manuscript Accepted: 19 DEC 2011
- Manuscript Revised: 2 DEC 2011
- Manuscript Received: 18 OCT 2011
- Colorado State Univ
- Regulatory T cell;
- Tyrosine kinase inhibitor
Tyrosine kinase inhibitors (TKIs) and metronomic dosing of cyclophosphamide (CYC) can improve tumor control by suppression of regulatory T cells (Treg) and restoration of T cell-mediated immune responses in mice and humans. The immunomodulatory effects of the TKI toceranib, as a single agent or in combination with metronomic CYC, have not been previously investigated in dogs.
The primary objectives of this study were to determine the effects of toceranib and metronomic CYC treatment on lymphocyte subsets including Treg and on interferon-gamma (IFN-γ) secretion in dogs with cancer. We hypothesized that toceranib would selectively decrease Treg numbers and increase IFN-γ production and that addition of CYC would further enhance these effects.
Fifteen client-owned dogs with advanced tumors were entered into a prospective clinical trial.
Dogs received toceranib at 2.75 mg/kg once every other day. After 2 weeks, oral CYC was added at 15 mg/m2 daily. Numbers of Treg and lymphocyte subsets were measured in blood by flow cytometry during the 8-week study period. Serum concentrations of IFN-γ were measured by ELISA.
Administration of toceranib significantly decreased the number and percentage of Treg in the peripheral blood of dogs with cancer. Dogs receiving toceranib and CYC demonstrated a significant increase in serum concentrations of IFN-γ, which was inversely correlated with Treg numbers after 6 weeks of combination treatment.
In addition to antitumor effects, these data support further investigations into the immunomodulatory effects of toceranib, administered alone or in combination with CYC in dogs with cancer.