There are no treatments available to men with non-metastatic hormone-refractory (NMHR) prostate cancer(PC). For such patients immunotherapy may be beneficial. This proposal aims to enhance the clinicaleffectiveness of therapeutic vaccination against PC and test it in patients in the NMHR stage such thatprogression to metastatic hormone-refractory prostate cancer (HRPC) may be delayed. The study aims tocombine two hitherto separately applied modes of immunotherapy: vaccination with autologous dendriticcells and vaccination with allogeneic PC cells (APCCs). Recently our collaborators reported that a vaccineconsisting solely of APCCs reduced PSA velocity in 42 percent of patients and extended the median time toprogression in men suffering from NMHR-PC to 58 weeks compared to historical controls of 26 weeks(Michael et al., Clin Cancer Res, 11: 4469-4478; 2005). We hypothesize that clinical efficacy of this APCCvaccine will be enhanced by combination with fully mature autologous myeloid dendritic cells (amDCs) thatare engineered to secrete IL-6 and IL-12; these cytokines are expected to stimulate expansion of cytotoxic Tcells over the suppressing T regulatory cells.
The specific aims of this study are: 1) To conduct a two-armrandomized phase 2 clinical trial of the APCC vaccine administered alone (Arm I) or in combination withamDCs (Arm II) to patients suffering from NHHR-PC. Based on our recent findings that human serumkallikrein-2 (hK2) levels correlate with overall survival in patients suffering from HRPC, we will determine therole of hK2 as a survival predictor in HRPC patients treated with immunotherapy. 2) To identify andcharacterize the type, extent, and duration of the immune response in patients treated in Arm I and Arm II.We will enroll 30 patients to each arm of this open-label phase 2 trial. Metastasis-free survival is the primaryendpoint, while vaccine toxicity and tolerability, PSA-based progression-free survival, change in PSAvelocity and duration of PSA response, changes in the predictive survival score and changes of immunefunction are among secondary endpoints. The proposed trial combines the advantages of APCCs as asource of tumor antigens with DCs that present antigens both to CD4+ and CD8+ T cells. The applicants arefully equipped, trained and experienced in clinical grade manufacturing of APCCs and DCs and have testedthem in earlier separate clinical trials assuring timely initiation and technical success of the study.
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