In this proposal we will test the hypothesis that RNA transfected Dendritic cells (DC) are highly effective stimulators of antitumor immunity and are capable of inducing tumor specific, T-cell mediated immune responses in patients with advanced or metastatic prostate cancer. This assumption is based on a large body of data from our laboratory providing a proof of concept that tumor RNA transfected DC not only mediate tumor specific CTL responses, but also provide considerable therapeutic benefit in tumor bearing animals. In addition, our group has conducted extensive laboratory studies not only exploring the use of DC based tumor vaccines, but also modifying DC to present high amounts of antigen level, therefore serving as potent inducers of antigen specific immunity in vitro and vivo models. In this proposal we will test the technical feasibility and effectiveness of this tumor vaccination strategy in the field of prostate cancer. The experimental strategy will consist of preclinical studies and clinical trials. We will optimize DC-based tumor vaccines transfected with RNA preparations encoding prostate or prostate cancer specific tumor antigens from various sources. We will pulse DC with RNA encoding the defined model antigen prostate specific antigen, PSA, or will utilize RNA amplified from autologous tumor specimen. These RNA preparations will then be tested in vitro for their ability to induce antigen specific T cell responses. In the clinical study section we will initially focus on the use of DC based vaccines pulsed with the marker antigen PSA. In this protocol we will monitor the presence, persistence and function of PSA specific T-cells and will develop new strategies for immunological monitoring to be used as endpoints in subsequent trials. We hope that information gained from these studies will provide more insight into generating more effective tumor vaccines through which a therapeutic benefit could be achieved for patients with advanced prostate cancer.
| Su, Zhen; Vieweg, Johannes; Weizer, Alon Z et al. (2002) Enhanced induction of telomerase-specific CD4(+) T cells using dendritic cells transfected with RNA encoding a chimeric gene product. Cancer Res 62:5041-8 |
| Heiser, A; Maurice, M A; Yancey, D R et al. (2001) Induction of polyclonal prostate cancer-specific CTL using dendritic cells transfected with amplified tumor RNA. J Immunol 166:2953-60 |
| Heiser, A; Maurice, M A; Yancey, D R et al. (2001) Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors. Cancer Res 61:3388-93 |
| Heiser, A; Dahm, P; Yancey, D R et al. (2000) Human dendritic cells transfected with RNA encoding prostate-specific antigen stimulate prostate-specific CTL responses in vitro. J Immunol 164:5508-14 |
