Clinical and immunomodulatory effects of toceranib combined with low-dose cyclophosphamide in dogs with cancer

J Vet Intern Med. 2012 Mar-Apr;26(2):355-62. doi: 10.1111/j.1939-1676.2011.00883.x. Epub 2012 Feb 4.


Background: 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.

Hypothesis: 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.

Animals: Fifteen client-owned dogs with advanced tumors were entered into a prospective clinical trial.

Methods: Dogs received toceranib at 2.75 mg/kg once every other day. After 2 weeks, oral CYC was added at 15 mg/m(2) 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.

Results: 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.

Conclusions: 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / administration & dosage*
  • Blood Cell Count / veterinary
  • Cyclophosphamide / administration & dosage*
  • Dog Diseases / blood
  • Dog Diseases / drug therapy*
  • Dog Diseases / immunology
  • Dogs
  • Drug Therapy, Combination / veterinary
  • Female
  • Flow Cytometry / veterinary
  • Immunologic Factors / administration & dosage*
  • Indoles / administration & dosage*
  • Interferon-gamma / blood
  • Male
  • Neoplasms / blood
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / veterinary*
  • Prospective Studies
  • Pyrroles / administration & dosage*
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology


  • Antineoplastic Agents, Alkylating
  • Immunologic Factors
  • Indoles
  • Pyrroles
  • toceranib phosphate
  • Interferon-gamma
  • Cyclophosphamide