Prostate cancer is the second leading cause of cancer death in American males, and there is an urgent need for novel therapeutics. Although androgen ablation temporarily controls metastatic disease, almost all tumors eventually become hormone-refractory and then rapidly progress since there is no other effective treatment. Prostate-specific membrane antigen (PSMA) is a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm in normal prostate epithelial cells. In contrast, on prostate cancer cells, PSMA exists as a membrane glycoprotein with a large extracellular domain. This pattern of expression makes PSMA a compelling target for active immunotherapy. Our overall goal is to develop and clinically evaluate PSMA-based vaccines. We are pursuing both traditional purified protein vaccines and novel viral vector vaccines for eventual use alone and in heterologous prime-boost combinations in man. Alphavirus replicons and adjuvanted protein vaccines are ideal complements with the potential to mediate a wide array of potent, protective cellular and humoral immune responses in vivo. In this Phase I project, we will perform critical preclinical development activities to produce and characterize new alphavirus replicons, based on Semliki Forest virus, that express distinct forms of PSMA. A human HLA-A2 transgenic animal model will be employed to measure the quality and the magnitude of immune responses elicited in vivo by prime-boost combinations of PSMA vaccines, and these data will drive the selction of novel immunotherapies for clinical trials.
