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


OBJECTIVE
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.


METHODS
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.
Animal Cancer Center, Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523-1620, USA.
L
L
Mitchell
D H
DH
Thamm
B J
BJ
Biller
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D001772:Blood Cell Count / Q000662:veterinary; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004283:Dog Diseases / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004285:Dogs; D004359:Drug Therapy, Combination / Q000662:veterinary; D005260:Female; D005434:Flow Cytometry / Q000662:veterinary; D007155:Immunologic Factors / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000662:veterinary*; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage*; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
D018906:Antineoplastic Agents, Alkylating; D007155:Immunologic Factors; D007211:Indoles; D011758:Pyrroles; C464577:toceranib phosphate; D007371:Interferon-gamma; D003520:Cyclophosphamide