Prostate cancer is the most common cancer of men in the United States with approximately 189,000 new cases and 30,000 deaths in 2002. Recurrent disease can be controlled temporarily with androgen ablation. However, almost all prostate carcinomas eventually become hormone refractory and then rapidly progress. Prostate cancer is largely resistant to conventional chemotherapy, and currently there is no effective treatment for advanced, metastatic disease. Thus, there is an urgent need for therapies that can prevent or treat advanced prostate cancer. Prostate-specific membrane antigen (PSMA) is a well-characterized glycoprotein whose expression is largely restricted to prostate epithelial cells. In normal prostate, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. In prostate cancer, however, PSMA is expressed as a type 2 membrane protein with a large extracellular domain. PSMA expression increases approximately 1000-fold with disease progression. PSMA also possesses carboxypeptidase activities that may play a role in metastasis. For these reasons, PSMA represents a highly attractive target for active immunotherapy of prostate cancer. The goal of this Phase II project is advance our recombinant soluble PSMA (rsPSMA) vaccine into human clinical testing to prevent and/or reverse disease progression. The rsPSMA vaccine is a novel construct that comprises the extracellular domain of PSMA plus an immunostimulatory adjuvant. In the Phase I project, we developed procedures for producing and purifying rsPSMA in a manner that preserves its native conformation. Like native, cell-surface PSMA, the rsPSMA protein was discovered to form a noncovalent dimer, and only the dimeric form of rsPSMA was enzymatically active and capable of inducing high levels of antibodies that cross-react with PSMA-expressing tumor cells. The findings provide important proof-of-concept for our rsPSMA vaccine. In addition, these novel insights into PSMA structure-function relationships have important implications for PSMA vaccine design and development. The Phase II project seeks to complete critical preclinical development and clinical manufacturing activities required to initiate human testing. We will also optimize the ability of the vaccine to break tolerance in an innovative PSMA transgenic animal model. These activities culminate in a first-in-humans study of this novel vaccine therapy in prostate cancer. If successful in inducing anti-PSMA antibodies in man, the rsPSMA vaccine would represent a promising new mode of therapy for use alone or in prime-boost combinations with vaccines that induce potent cellular immunity.
