The currently proposed project represents a phase I study in humans with metastatic kidney (renal) cancer to evaluate a novel form of gene modified tumor cell vaccine. This study is based on extensive preclinical experiments in animal tumor models for gene targeted immunotherapy. The animal tumor experiments have shown that introducing specific genes into tumor cells that encode stimulating growth factors (termed cytokines) for the immune system enhance the ability of these gene modified tumor cells to activate an immune response in the animal against the original tumor. Specifically, we have found that a particular cytokine gene, GM-CSF, when introduced into the tumor, results in the most effective generation of clinically relevant systemic antitumor immune responses. Using highly efficient and safety tested viruses as a vehicle to transfer genes into the tumor cells, we have been able to genetically modify human cancer cells to produce equivalent levels of the immunostimulatory GM-GSF as has been accomplished in the animal tumor cells. The current human protocol seeks to accomplish specific clinical and laboratory objectives. First, as a phase I protocol, it seeks to determine the maximum tolerated dose of irradiated autologous renal tumor cells, unmodified and after transfer of the human GM-CSF gene. Second, we seek to quantitate the toxicities, if any, of introducing increasing amounts of GM-CSF gene transduced tumor cells. Thirdly, we seek to quantitate the specific antitumor immune responses induced by these vaccination approaches. Fourth, we will seek preliminary evidence of therapeutic activity of the vaccine preparation. This trial is designed with two arms: one arm evaluates escalating doses of GM-CSF transduced tumor cells and the second parallel arm evaluates escalating doses of nontransduced tumor cells. While the primary objective of the two arm trial is to determine whether observed toxicity is due to cell administration of the GM-CSF gene transfer, we will also seek preliminary comparative evidence to determine whether the introduction of the GM-CSF gene into the tumor cells modifies their vaccination potential relative to untransduced tumor cells with regards to either immunologic or clinical antitumor responses.
