Gene therapy for human prostate cancer. Translational research in the hormone refractory dunning prostate cancer model

Abstract

Background. Genetically engineered tumor vaccines are feasible for clinical trials in human prostate cancer, and Phase I testing has been approved. The Dunning rat prostate cancer model provides an opportunity for translational research to rationally design Phase II clinical studies testing efficacy. Methods. The Dunning R3327 MAT-LyLu subline was transduced with the retroviral vector MFG carrying the cytokine gene for human granulocyte-macrophage s colony-stimulating factor (GM-CSF). Varying secretion rates of human GM-CSF were generated and tumor cell vaccines were formulated, consisting of 5 × 106 lethally irradiated transduced cells. The vaccines were placed at a subcutaneous site opposite preestablished tumor of 1 × 104 cells implanted 3 days earlier in Copenhagen rats. Trials were masked, randomized, and conducted over 6-week intervals using different treatment schedules, vaccine number, and varying doses of human GM-CSF secretion as well as appropriate controls. Results. Thirty percent of rats with long term follow-up can be cured of preestablished tumor burdens with human GM-CSF transduced tumor vaccines secreting greater than 140 ng/106 cells/24 hours of human GM-CSF. All studies evaluating more than one vaccine over a wide range of human GM-CSF secretion rates show significant delays in tumor appearance and progression. One vaccination is not curative. Vaccination with GM-CSF transduced tumor vaccines increased disease free survival and slowed tumor progression over animals vaccinated with irradiated tumor cells admixed with either soluble GM-CSF or with a nonspecific immune adjuvant (Corynebacterium parvum). The ability to cure animal and delay progression appears related to total duration of human GM-CSF secretion at the subcutaneous site. Systemic human GM-CSF could be detected in the serum of rats for at least 6 days after vaccination. Conclusions. These data have implications for the design of gene therapy trials in prostate cancer. Small androgen independent tumor burdens such as volumes seen in the adjuvant setting can be cured. Multiple vaccinations with adequate human GM-CSF secretion are required. At higher human GM-CSF secretion rates, systemic levels may be achievable, and patients should be evaluated closely for toxicity to and the pharmacokinetics of GM-CSF. Cancer 1995;75:2013–20.