Vaccination of prostatectomized prostate cancer patients in biochemical relapse, with autologous dendritic cells pulsed with recombinant human PSA

Abstract

This study was conducted in prostate cancer patients in biochemical relapse after radical prostatectomy, to assess the feasibility, safety, and immunogenicity of therapeutic vaccination with autologous dendritic cells (DCs) pulsed with human recombinant prostate-specific antigen (PSA) (Dendritophage-rPSA). Twenty-four patients with histologically proven prostate carcinoma and an isolated postoperative rise of serum PSA (>1 ng/ml to 10 ng/ml) after radical prostatectomy were included. The patients received nine administrations of PSA-loaded DCs by combined intravenous, subcutaneous, and intradermal routes over 21 weeks. Postbaseline blood tests were performed at months 1, 3, 6, 9, and 12 (PSA levels), at months 6 and 12 (circulating prostate cancer cells), at month 6 (anti-PSA IgG and IgM antibodies), and at up to eight time points before, during, and after immunization (PSA-specific T cells). Circulating prostate cancer cells detected in six patients at baseline were undetectable at 6 months and remained undetectable at 12 months. Eleven patients had a postbaseline transient PSA decrease on one to three occasions, predominantly occurring at month 1 (7 patients) or month 3 (2 patients). Maximum PSA decrease ranged from 6% to 39%. PSA decrease on at least one occasion was more frequent in patients with low Gleason score ( p=0.016) at prostatectomy and with positive skin tests at study baseline ( p=0.04). PSA-specific T cells were detected ex vivo by ELISpot for IFN-gamma in 7 patients before vaccination and in 11 patients after vaccination. Of the latter 11 patients, 5 had detectable T cells both before and during the vaccination period, 4 only during the vaccination period, while 2 patients could for technical reasons not be assessed prevaccination. No induction of anti-PSA IgG or IgM antibodies was detected. There were no serious adverse events or otherwise severe toxicities observed during the trial. Immunization with Dendritophage-rPSA was feasible and safe in this cohort of patients. An immune response specific for PSA could be detected in some patients. A notable effect was the disappearance of circulating prostate cells in all patients who were RT-PCR positive before vaccination.

Immunotherapy for Prostate Cancer: Lessons from Responses to Tumor-Associated Antigens

“…Constructs targeting the NY-ESO-1 antigen has led to significant immunological responses, which makes NY-ESO-1 an interesting antigen to target immunotherapeutic strategies in future (49, 132). Immunological responses are also induced by several PSA-targeting vaccines, supporting the usage of PSA as an immunogenic tumor antigen (34–36). …”

“…Vaccinations with vaccinia-based vectors expressing PSA resulted in stabilization of serum PSA levels and PSA-specific T-cell responses were observed (34). PSA-specific T cells were also detected after vaccination with a liposome-based PSA vaccine and a dendritic cell (DC)-based vaccine (35, 36). Treatment with a PSA encoding poxviral vector vaccine in combination with radiotherapy not only showed PSA-specific T-cell activation, but also T-cell responses against prostate-associated antigens not encoded by the vaccine.…”

CD40-activated B cells induce anti-tumor immunityin vivo

“…No abnormal changes in organ sections or flow cytometry analyses of lymphoid organs were observed (data not shown). In comparison, in clinical trials with DC-based vaccines in patients with prostate and renal cell cancer average doses of 0.06 – 0.13 × 10 6 cell/kg were administered [34–42] with the lowest dose of 0.0075 × 10 6 cell/kg [43] and the highest dose of 1.5 × 10 6 cell/kg [44]. In a study with dogs with spontaneous cancer 1-5 × 10 6 CD40B cells were injected per dog, which equals 0.03-0.15 × 10 6 cells/kg [30].…”

Extracellular Proteases as Targets for Drug Development

“…Recently, a novel approach for designing kallikrein-specific inhibitors based on inhibitor protein-protease reactive site interactions has been described 124 . Other therapeutic strategies exploit hK activity and/or tissue specificity in the development of the hK3 activated prodrugs 125–128 , cytoreductive gene-therapy approaches for the selective destruction of prostate tumors 129 , and active immunotherapy using hK-based vaccines 130–132 .…”