H. Ragde

Phase I clinical trial: T‐cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA‐A0201‐specific peptides from prostate‐specific membrane antigen

Conventional treatment for metastatic prostate cancer have failed to demonstrate curative potential in all patients. Investigations involving the role of T‐cell immunity in the clearance of neoplastic cells are now available. Development of T‐cell immunotherapy may give a new approach to the treatment of advanced metastatic prostate cancer.

Infusion of dendritic cells pulsed with HLA‐A2‐specific prostate‐specific membrane antigen peptides: A phase II prostate cancer vaccine trial involving patients with hormone‐refractory metastatic disease

A phase II trial was conducted to assess the efficacy of infusions of dendritic cells (DC) and two HLA‐A2‐specific PSMA peptides (PSM‐P1 and ‐P2). This report describes thirty three subjects with hormone‐refractory metastatic prostate cancer without prior vaccine therapy history who were evaluated and reported as a group.

Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides.

A phase I trial involving patients with advanced prostate cancer was conducted to assess the safe administration of dendritic cells (DC) and HLA‐A0201‐specific prostate‐specific membrane antigen (PSMA) peptides (PSM‐P1 or ‐P2). Thirty‐three of the phase I participants were subsequently enrolled in a phase II trial, which involved six infusions of DC pulsed with PSM‐P1 and ‐P2 peptides.

Phase II Prostate cancer vaccine trial : Report of a study involving 37 patients with disease recurrence following primary treatment

A phase II trial was conducted to assess the efficacy of infusions of dendritic cells (DC) and two HLA‐A2‐specific prostate‐specific membrane antigen (PSMA) peptides (PSM‐P1 and ‐P2). This report describes the evaluation of 37 subjects admitted with presumed local recurrence of prostate cancer after primary treatment failure.

Follow-up evaluation of a phase II prostate cancer vaccine trial.

A phase II trial, involving infusions of autologous dendritic cells (DC) and two human histocompatibility antigen (HLA‐A2)‐specific prostate‐specific membrane antigen (PSMA) peptides, was recently completed. Thirty percent of the participants, including subjects with hormone‐refractory metastastic disease, and those with suspected local recurrence of prostate cancer, were identified as clinical responders. This report describes the follow‐up evaluation of 19 responders in the two study groups.

Presentation of prostate tumor antigens by dendritic cells stimulates T-cell proliferation and cytotoxicity.

Dendritic cells (DCs) are “professional” antigen‐presenting cells capable of stimulating T‐cell proliferation and cytotoxicity when loaded with and presenting specific antigens, including tumor antigens. We demonstrated the stimulation of an autologous cytotoxic T‐cell response elicited by DC loaded with autologous tumor cell lysate derived from primary prostate tumor. A candidate tumor antigen is prostate‐specific membrane antigen (PSMA), which is overexpressed in prostate cancer patients. We identified a HLA‐A2 motif in PSMA, isolated patient DC, loaded peptide into DC, and stimulated autologous T cells to proliferate. The ability to use DC for presentation of either tumor or peptide antigen in an HLA‐restricted fashion in order to stimulate T‐cell proliferation and cytotoxicity demonstrates the potential of this technology for development of a prostate cancer vaccine.

Follow-up evaluation of prostate cancer patients infused with autologous dendritic cells pulsed with PSMA peptides

We recently conducted a phase I clinical trial administering autologous dendritic cells pulsed with prostate‐specific membrane antigen (PSMA) peptides to advanced prostate cancer patients. Participants were divided into 5 groups receiving 4 or 5 infusions of peptides alone (PSM‐P1 or ‐P2; groups 1 and 2, respectively), autologous DC (group 3), or DC pulsed with PSM‐P1 or ‐P2 (groups 4 and 5, respectively). Seven partial responders were observed. Follow‐up evaluation of these responders is presented in this report.

Transrectal ultrasound microbubble contrast angiography of the prostate.

Prostate cancer, suspected by serum prostate‐specific antigen (PSA) elevation and/or digital abnormalities, is not always evident on gray‐scale or color Doppler transrectal ultrasound (TRUS). EchoGen® (Sonus Pharmaceuticals, Inc., Bothell, WA), a blood vessel image enhancer able to visualize smaller, low‐flow vessels and thus possibly the microvascular angiogenesis often associated with cancer, was employed to see if it would improve prostate cancer detection, particularly in patients with a rising serum PSA and prior negative biopsies.

Comparison of serum PSMA, PSA levels with results of cytogen-356 ProstaScint® scanning in prostatic cancer patients

Stored serum from clinical trial cases undergoing ProstaScint® (CYT‐356) scanning were available for Prostate Specific Membrane Antigen (PSMA) assay. Prostate Specific Antigen (PSA) levels had already been determined. This provided an opportunity to see what correlations existed between the serum markers and the ProstaScint® scan. A group of patients had the studies preprostatectomy, whereas another group had the studies postprostatectomy.

Measurement of prostate‐specific membrane antigen in the serum with a new antibody

Work to date has identified prostate‐specific membrane antigen (PSMA) as a membrane‐bound glycoprotein with high specificity for prostatic epithelial cells. PSMA reacts with the monoclonal antibody 7E11.C5, which is present in serum, seminal fluid, and prostatic epithelial cells, and is increased in its expression in the presence of a hormone refractory state associated with prostatic cancer. This report confirms these results and further documents the presence of the monoclonal antibody 3F5.4G6, which reacts with the extracellular domain of PSMA. This region of PSMA is also an element present in a truncated version of the protein, so‐called PSM′. Immune precipitation with either 7E11.C5 or 3F5.4G6 yields an isolated protein species that are reactive with the reciprocal antibody in Western blot analysis. Thus, 3F5.4G6 recognizes the same PSMA protein as does 7E11.C5, but at different epitopes on essentially opposite ends of the molecule. These two antibodies are well suited for use in a sandwich immunoassay, either one as a capture or detection antibody. Current work on this is underway.