A Randomized Phase II Clinical trial to Determine the Safety, Tolerability and Ef

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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 clinical effectiveness of therapeutic vaccination against PC and test it in patients in the NMHR stage such that progression to metastatic hormone-refractory prostate cancer (HRPC) may be delayed. The study aims to combine two hitherto separately applied modes of immunotherapy: vaccination with autologous dendritic cells and vaccination with allogeneic PC cells (APCCs). Recently our collaborators reported that a vaccine consisting solely of APCCs reduced PSA velocity in 42 percent of patients and extended the median time to progression 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 APCC vaccine will be enhanced by combination with fully mature autologous myeloid dendritic cells (amDCs) that are engineered to secrete IL-6 and IL-12; these cytokines are expected to stimulate expansion of cytotoxic T cells over the suppressing T regulatory cells. The specific aims of this study are: 1) To conduct a two-arm randomized phase 2 clinical trial of the APCC vaccine administered alone (Arm I) or in combination with amDCs (Arm II) to patients suffering from NHHR-PC. Based on our recent findings that human serum kallikrein-2 (hK2) levels correlate with overall survival in patients suffering from HRPC, we will determine the role of hK2 as a survival predictor in HRPC patients treated with immunotherapy. 2) To identify and characterize 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 primary endpoint, while vaccine toxicity and tolerability, PSA-based progression-free survival, change in PSA velocity and duration of PSA response, changes in the predictive survival score and changes of immune function are among secondary endpoints. The proposed trial combines the advantages of APCCs as a source of tumor antigens with DCs that present antigens both to CD4+ and CD8+ T cells. The applicants are fully equipped, trained and experienced in clinical grade manufacturing of APCCs and DCs and have tested them in earlier separate clinical trials assuring timely initiation and technical success of the study.