Particle-mediated gene transfer of granulocyte-macrophage colony-stimulating factor cDNA to tumor cells: Implications for a clinically relevant tumor vaccine

The necessity for prolonged tissue culture manipulations limits the clinical application of many farms of gene therapy in patients with malignancies. We hypothesized that granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA in a plasmid expression vector could be effectively introduced into resting tumor cells, without the need for tissue culture propagation prior to or following transfection, and that efficient expression of transgenic GM-CSF by the transfected tumor cells would confer an effective immune response against tumors, GM-CSF cDNA in expression vectors was coated onto gold particles and accelerated with a gene gun device into mouse and human tumor cells, Human tumor tissue transfected within 4 hr of surgery produced significant levels of transgenic human GM-CSF protein in vitro, Human GM-CSF was readily detectable in serum and at the injection site following subcutaneous implantation of these transfected tumor cells into nude mice, Transfected and irradiated murine B16 melanoma cells produced greater than or equal to 100 ng/ml murine GM-CSF/10(6) cells per 24 hr in vitro for at least 10 days, The antitumor efficacy of this nonviral approach was tested using irradiated B16 tumor cells that were transfected with mGM-CSF cDNA and injected into mice as a tumor ''vaccine.'' Subsequent challenge of these mice with nonirradiated, nontransfected B16 tumor cells showed that 58% of the animals were protected from the tumor by the prior vaccine treatment, In contrast, only 2% of control animals mere protected by prior treatment with irradiated B16 cells transfected with the vector containing the luciferase gene, These results suggest that particle-mediated transfection of fresh tumor explants with cytokine cDNA is an effective and clinically attractive approach for cancer therapy.