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 inten se investigation in both basic research and clinical medicine, Our eff orts to utilize tumor vaccines in an immunotherapeutic manner involve canines with spontaneous tumors. We hypothesized that canine tumor cel ls, transfected with human granulocyte-macrophage colony-stimulating f actor (hGM-CSF) cDNA in a plasmid vector, would prove nontoxic followi ng intradermal administration, generate biologically relevant levels o f protein, effect local histological changes at the sites of vaccinati on, and create a systemic antitumor response. Sixteen tumor-bearing do gs were admitted to a study of ex vivo gene therapy. Tumor tissue was surgically removed, enzymatically and mechanically dissociated, irradi ated, transfected, and intradermally injected back into the patients, The dogs were vaccinated with primary autologous tumor cells transfect ed with hGM-CSF or a reporter control gene. hGM-CSF protein was detect ed (0.07 to 14.15 ng/vaccination site) at 24 hr postinjection and dram atic histological changes were observed, characterized by neutrophil a nd macrophage infiltration at the sites of injection of hGM-CSF-transf ected tumor cells. This was in stark contrast to the lesser neutrophil ic and eosinophilic infiltrates found at control vaccination sites. Ob jective evidence of an antitumor response was observed in three animal s. These data, in a large animal translational model of spontaneous tu mors, demonstrate in vivo biological activity of hGM-CSF-transfected a utologous tumor cell vaccines.