Naked DNA and adenoviral immunizations for immunotherapy of prostate cancer: A phase I/II clinical trial

Introduction and Objectives: Animal studies have indicated that the use of syngeneic dendritic cells that have been transfected ex vivo with DNA for t umor-specific antigen results in tumor regression and decreased number of m etastases. Additional studies have also suggested the possibility to modula te the dendritic cells in vivo either by 'naked' DNA immunization or by inj ecting replication-deficient viral vectors that carry the tumor-specific DN A. Using the prostate-specific membrane antigen (PSMA) as a target molecule , we have initiated a clinical trial for immunotherapy of prostate cancer. The primary objective of the study was to determine the safety of the PSMA vaccine after repeated intradermal injections. Methods: We have included the extracellular human PSMA DNA as well as the h uman CD86 DNA into separate expression vectors (PSMA and CD86 plasmids), an d into a combined PSMA/CD86 plasmid. In addition, the expression cassette f rom the PSMA plasmid was inserted into a replication deficient adenoviral e xpression vector. Twenty-six patients with prostate cancer were entered int o a phase I/II toxicity-dose escalation study, which was initiated in sprin g 1998. Immunizations were performed intradermally at weekly intervals. Dos es of DNA between 100 and 800 mu g and of recombinant virus at 5 x 10(8) PF Us per application were used. Results and Conclusion: No immediate or long-term side effects following im munizations have been recorded. All patients who received initial inoculati on with the viral vector followed by PSMA plasmid boosts showed signs of im munization as evidenced by the development of a delayed-type hypersensitivi ty reaction after the PSMA plasmid injection. In contrast, of the patients who received a PSMA plasmid and CD86 plasmid, only 50% showed signs of succ essful immunization. Of the patients who received PSMA plasmid and soluble GM-CSF, 67% were immunized. However, all patients who received the PSMA/CD8 6 plasmid and sGM-CSF became immunized. The patients who did not immunize d uring the first round were later successfully immunized after a boost with the viral vector. The heterogeneity of the medical status and the presence in many patients of concomitant hormone therapy does not permit unequivocal interpretation of the data with respect to the effectiveness of the therap y. However, several responders, as evidenced by a change in the local disea se, distant metastases, and PSA levels, can be identified. A phase II clini cal study to evaluate the effectiveness of the therapy is currently underwa y. Copyright (C) 2000 S. Karger AG. Basel.