Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.17.21 (prostate-specific membrane antigen)
 1,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Presentation of prostate tumor antigens by dendritic cells stimulates T-cell proliferation and cytotoxicity. 854 83

The development of immunotherapy for cancer, such as synthetic peptide-based vaccines, relies heavily on the identification of appropriate epitopes capable of eliciting antitumor T-cell responses. We have used a combination of computer-based algorithms to predict peptide sequences from prostate-specific membrane antigen (PSMA) capable of stimulating in vitro CTLs restricted by the HLA-A2 MHC molecule. Four of the five peptides that were predicted by these algorithms were capable of inducing antigen-specific CTLs that killed target cells that were pulsed exogenously with the corresponding peptides. However, only one of the four peptides, PSMA(27), induced CTLs that were effective at recognizing prostate tumor cells expressing the HLA-A2 and PSMA molecules. These results underline the importance of demonstrating antitumor reactivity of peptide-induced CTLs for the selection of epitopes destined to become immunotherapeutic for prostate cancer.
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PMID:Recognition of prostate tumor cells by cytotoxic T lymphocytes specific for prostate-specific membrane antigen. 1238 42

Prostate-related antigens, including prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP), can be targets in specific immunotherapy for prostate cancer. In this study, we attempted to newly identify epitope peptides from these 2 antigens, which are immunogenic in human histocompatibility leukocyte antigen (HLA)-A2+ prostate cancer patients. Twenty-nine peptides (PSMA with 15 and PAP with 14) were prepared based on the HLA-A2 binding motif. Based on our previous finding that antigenic peptides recognized by both cellular and humoral immune systems are useful for peptide-based immunotherapy, peptide candidates were screened first by their ability to be recognized by immunoglobulin G (IgG), and then by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs). As a result, PSMA441-450 and PAP112-120 peptides were found to be frequently recognized by IgG in plasma from prostate cancer patients. These 2 candidates effectively induced HLA-A2-restricted and prostate cancer-reactive CTLs in HLA-A2+ prostate cancer patients with several HLA-A2 subtypes. In addition, their cytotoxicity was mainly dependent on peptide-specific and CD8+ T cells. These results indicate that these PSMA441-450 and PAP112-120 peptides could be promising candidates for peptide-based immunotherapy for HLA-A2(+) prostate cancer.
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PMID:Prostate-related antigen-derived new peptides having the capacity of inducing prostate cancer-reactive CTLs in HLA-A2+ prostate cancer patients. 1528 44

We are evaluating the use of electroporation (EP) to deliver a novel DNA vaccine, p.DOM-PSMA(27). This vaccine encodes a domain (DOM) of fragment C of tetanus toxin to induce CD4(+) T cell help, fused to a tumor-derived epitope from prostate-specific membrane antigen (PSMA) for use in HLA-A2(+) patients with recurrent prostate cancer. We report on safety and tolerability and on antibody response to DOM as a first indication of the effect of EP in patients. In this open label phase I/II, two-arm, dose escalation trial DNA was delivered either by intramuscular injection or by intramuscular injection followed by EP (DNA+EP), with five patients per dose level. Three vaccinations were given at 0, 4, and 8 weeks,with booster doses at 24 and 48 weeks; here we allowed crossover between study arms if supported by the safety and immunological data. In the 20 patients in the first two dose cohorts we observed that beyond brief and acceptable pain at the injection site, EP did not appear to add toxicity to the vaccination. We evaluated humoral responses to DOM. Low anti-DOM IgG antibody responses were observed after intramuscular injection of DNA without EP (at week 12: mean 1.7- vs. 24.5-fold increase over baseline with DNA+EP). These could be boosted by delivery of DNA+EP at later time points. Delivery of DNA+EP at all five vaccinations yielded the highest levels of anti-DOM antibody. Responses persisted to 18 months of follow-up. These data establish EP as a potent method for stimulating humoral responses induced by DNA vaccination in humans.
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PMID:DNA vaccination with electroporation induces increased antibody responses in patients with prostate cancer. 1961 1

We report on the immunogenicity and clinical effects in a phase I/II dose escalation trial of a DNA fusion vaccine in patients with prostate cancer. The vaccine encodes a domain (DOM) from fragment C of tetanus toxin linked to an HLA-A2-binding epitope from prostate-specific membrane antigen (PSMA), PSMA(27-35). We evaluated the effect of intramuscular vaccination without or with electroporation (EP) on vaccine potency. Thirty-two HLA-A2(+) patients were vaccinated and monitored for immune and clinical responses for a follow-up period of 72 weeks. At week 24, cross-over to the immunologically more effective delivery modality was permitted; this was shown to be with EP based on early antibody data, and subsequently, 13/15 patients crossed to the +EP arm. Thirty-two HLA-A2(-) control patients were assessed for time to next treatment and overall survival. Vaccination was safe and well tolerated. The vaccine induced DOM-specific CD4(+) and PSMA(27)-specific CD8(+) T cells, which were detectable at significant levels above baseline at the end of the study (p = 0.0223 and p = 0.00248, respectively). Of 30 patients, 29 had a measurable CD4(+) T-cell response and PSMA(27)-specific CD8(+) T cells were detected in 16/30 patients, with or without EP. At week 24, before cross-over, both delivery methods led to increased CD4(+) and CD8(+) vaccine-specific T cells with a trend to a greater effect with EP. PSA doubling time increased significantly from 11.97 months pre-treatment to 16.82 months over the 72-week follow-up (p = 0.0417), with no clear differential effect of EP. The high frequency of immunological responses to DOM-PSMA(27) vaccination and the clinical effects are sufficiently promising to warrant further, randomized testing.
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PMID:DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8(+) T-cell responses and increases PSA doubling time. 2272 56