Prostate cancers that have spread beyond the confines of the gland regress following the withdrawal or blockade of androgens, and at relapse, following chemotherapy. In both settings the outcomes are similar: most cells undergo growth arrest, but only few undergo apoptotic death. We hypothesize that an immune based approach can eliminate the non-proliferating yet viable cells, particularly after tumor mass has been de-bulked. Prostate cancer offers several advantages in testing new tumor immunotherapies. Serum prostate specific antigen (PSA) levels provide a simple, yet excellent marker of response to therapy. Patients with rising PSA, who have a poor prognosis, can be identified while they are still functionally healthy. As elimination of growth-arrested cells is essential in such patients, they are ideally suited for tumor immunotherapy. Our objective is to demonstrate that immunization of prostate cancer patients with autologous dendritic cells (DC's) cross-presenting apoptotic prostate tumor cells safely induces cytolytic T cell responses to tumor antigens. We will establish a system for the detection of tumor-specific T cell responses in prostate cancer patients that parallels methods established in our laboratory for influenza-specific T cell responses in normal individuals. Apoptotic prostate tumor cells will be co-cultured with DC's, allowing uptake and presentation of multiple tumor antigens on all MHC I molecules. These DC's will then be used to immunize patients. We will monitor patients for acute toxicity and T cell responses to established (e.g. prostate-specific membrane antigen) and new marker antigens present in the apoptotic prostate tumor cells to determine activity of our immunization. Our immunization method and key assays for antigen-specific T cell response are independent of patient HLA haplotype, allowing patients of all haplotype to enter the study. Our strategy is distinct in the breadth of antigen presented and potency resulting from use of the cross-priming pathway--up to 10,000 times more efficient than peptide pulsed DCs. Our results should indicate whether this new approach to DC based, immunotherapy has a potential role in the treatment of prostatic cancer as well as other malignancies.
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| Orange, D E; Jegathesan, M; Blachere, N E et al. (2004) Effective antigen cross-presentation by prostate cancer patients' dendritic cells: implications for prostate cancer immunotherapy. Prostate Cancer Prostatic Dis 7:63-72 |
