Development of human granulocyte-macrophage colony-stimulating factor-transfected tumor cell vaccines for the treatment of spontaneous canine cancer.
Cytokine gene-engineered tumor vaccines are currently an area of intense investigation in both basic research and clinical medicine. Our efforts to utilize tumor vaccines in an immunotherapeutic manner involve canines with spontaneous tumors. We hypothesized that canine tumor cells, transfected with human granulocyte-macrophage colony-stimulating factor (hGM-CSF) cDNA in a plasmid vector, would prove nontoxic following intradermal administration, generate biologically relevant levels of protein, effect local histological changes at the sites of vaccination, and create a systemic antitumor response. Sixteen tumor-bearing dogs were admitted to a study of ex vivo gene therapy. Tumor tissue was surgically removed, enzymatically and mechanically dissociated, irradiated, transfected, and intradermally injected back into the patients. The dogs were vaccinated with primary autologous tumor cells transfected with hGM-CSF or a reporter control gene. hGM-CSF protein was detected (0.07 to 14.15 ng/vaccination site) at 24 hr postinjection and dramatic histological changes were observed, characterized by neutrophil and macrophage infiltration at the sites of injection of hGM-CSF-transfected tumor cells. This was in stark contrast to the lesser neutrophilic and eosinophilic infiltrates found at control vaccination sites. Objective evidence of an antitumor response was observed in three animals. These data, in a large animal translational model of spontaneous tumors, demonstrate in vivo biological activity of hGM-CSF-transfected autologous tumor cell vaccines.
Hogge
G S
GS
School of Veterinary Medicine, University of Wisconsin-Madison, 53706, USA.
Burkholder
J K
JK
Culp
J
J
Albertini
M R
MR
Dubielzig
R R
RR
Keller
E T
ET
Yang
N S
NS
MacEwen
E G
EG
D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D017690:Cell Transplantation / Q000662:veterinary; D018076:DNA, Complementary; D004283:Dog Diseases / Q000473:pathology / Q000628:therapy*; D004285:Dogs; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D009368:Neoplasm Transplantation / Q000662:veterinary; D009369:Neoplasms / Q000473:pathology / Q000628:therapy / Q000662:veterinary*; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured; D014611:Vaccination / Q000662:veterinary
D019496:Cancer Vaccines; D018076:DNA, Complementary; D016178:Granulocyte-Macrophage Colony-Stimulating Factor