While surgery is an important treatment for prostate cancer, it is possible that removal of the primary tumor may preclude an opportunity for generating effective long-term protection against tumor recurrence. The proof-of principle concept tested here is that prostate cancer, prior to removal, can be engineered to self destruct and stimulate a potent and sustained immune response. We hypothesize that the microenvironment of dead and dying tumor cells, containing molecules capable of generating highly specific immune responses will diminish the potential for local and/or metastatic tumor recurrence. Prostate cancer cells following their incorporation of the gene for mda-7, a novel tumor suppressing cytokine that induces apoptosis and cell death in cancer cells without harming normal cells, will self-destruct in vivo. Simultaneously, the prostate cancer cells will have been engineered to produce a potent immunostimulatory agent, grp170, that serves as a """"""""vaccine"""""""" inducing antigen specific immunity. Using clinically relevant models, we will determine the therapeutic efficacy of intratumor delivery of genes expressing secretable grp170 and mda-7 to eradicate prostate cancer and metastasis (aim 1). We will identify and characterize the underlying immune mechanisms involved in development of long-term antitumor responses (aim 2). The proposal will provide the first experimental evidence testing the concept that systemic antitumor immune responses can be generated by combined delivery of 2 therapeutic molecules in situ that target both the tumor and the immune system. Mda-7 is already being evaluated in the clinic and has shown safety as well as antitumor activity against advanced cancer. The proposed research could lead to the design of a clinical trial for patients with prostate cancer in the very near future. ? ? ?
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