Many strategies to develop new treatments for hormone independent prostate cancer are being investigated, including gene therapy and immunotherapy. While immune activation and antitumor responses have been enhanced by the utilization of gene transfer techniques, the development of immunotherapy regimens capable of eliminating tumors has been problematic. Many reasons for the weak immunotherapy responses have been advocated including inefficient gene transfer. In preliminary studies, we utilized Gelfoam as a biodegradable collagen delivery system (CODES) that was observed to enhance gene transfer in solid tumors and benign dog prostate. Moreover, CODES-mediated gene transfer augmented T cell immunity, significantly enhancing antitumor activity against established prostate cancers. The studies outlined in this application will evaluate the mechanisms by which CODES functions in animal models, and also will test the ability of CODES to enhance gene transfer and augment immunity in prostate cancer patients. Preliminary studies showed CODES to induce expression and release of immunomodulatory factors by platelets, which modulated immunity and gene expression, suggesting a link between CODES, platelet-derived innate immune mediators, and adaptive T cell immunity. If validated, the observation will, for the first time, link platelet activation to the activation of adaptive immunity. Moreover, it may provide a basis for the development of novel ways to enhance gene transfer and augment tumor immunity as well as add to current knowledge of factors capable of modulating immune response to foreign antigens. Studies translating the observations with CODES in animal models into clinical trials will test the hypothesis that CODES enhances gene delivery in human prostate tissue using E1A/E1B-deleted type 5 adenovirus carrying the gene for human tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL). A second clinical study testing the hypothesis that CODES augments immunity in prostate cancer patients will be performed using adenovirus carrying the gene for prostate specific antigen.
