Prostate cancer is a major health issue for men in the United States. It is the second leading cause of cancer-related death in American men and represents the most prevalent form of cancer in males. Current treatment procedures have been limited in their effectiveness to prevent men from dying from prostate cancer. We are currently developing vaccines for patients with prostate cancer. In our approach, the patient's immune system will be used to attack and kill microscopic prostate tumor cells remaining after surgery to prevent spreading of cancer to other tissues. The DNA-based vaccine that we are investigating would stimulate the immune system to attack prostate cells through the recognition of a prostate-specific protein, prostatic acid phosphatase (PAP).

The rat is a great model to study the efficacy of this vaccine because we can detect and visualize the immune response directed against the prostate as evidence of prostatitis, inflammation in the prostate. We have shown that rats immunized with this vaccine directed to the human PAP (a foreign protein in the rat or "xenoantigen") will generate an immune response to human PAP but only a few rats develop a cross-reactive immune response to rat PAP (the native protein in the rat or "autoantigen") as indicated by prostatitis. In this proposal, we are exploring immunization strategies that would result in a more potent, consistent immune response.

In the first part of the proposal, we plan to study the mechanism behind the ability of a xenoantigen to generate an autoreactive immune response. Cells in the immune system (CD8+ and CD4+ T cells) create an immune response against a specific protein by recognizing specific regions of protein called epitopes. We are interested in identifying these epitopes of human and rat PAP recognized by T cells that are responsible for the immune response to the native protein.

In the second part, we plan to test whether rats immunized with the immunogenic epitopes develop an immune response to rat PAP. In addition, we will explore methods to improve the potency of the immune response by testing various "prime/boost" strategies by combining PAP DNA vaccines, PAP protein, and epitopes specific for PAP.

Overall, the goal of these studies is to develop improved vaccines. The information obtained from these studies will have a direct relevance to future human clinical vaccine trials targeting hPAP for the treatment of prostate cancer.