Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate-specific antigen (PSA) is a valuable marker antigen for prostate cancer. Lately considerable interest has been generated in the prospect of developing a vaccine for prostate cancer with PSA-derived peptide epitopes to induce cytotoxic T-cell (CTL) response. We report here that T cells capable of exhibiting PSA epitope-specific effector function-in their native state, i.e, without having to be further stimulated, in vitro-are detectable in more than half of the prostate cancer patients we studied. Ex vivo cultured autologous dendritic cells (DC) were used to present four HLA-A2-binding PSA peptide epitopes to freshly isolated peripheral blood lymphocytes (PBL) from patients and healthy volunteers. Ten out of 14 patients' PBL recognized at least one of the four peptides and 6 out of 10 patients' PBL recognized more than one peptide antigen as measured by IFN-gamma secretion upon stimulation of the PBL with the peptide antigen. Intracytoplasmic cytokine analysis for IFN-gamma in purified CD8(+) cells after stimulation with peptide antigens was tested in 6 patients and this technique demonstrated a similar response. Freshly isolated and purified CD8(+) cells when tested, also recognized the epitopes, as measured by IFN assay, when presented by transporter associated with antigen-processing (TAP) deficient T2 cells in an MHC-I restricted fashion. PBL from 9 normal donors when tested in identical fashion did not show any IFN-gamma production in recognition to the peptide antigens. Interestingly, neither of these CD8(+) T cells having IFN-gamma-producing ability did show any cytolytic activity in their native state against peptide loaded target cells or tumor cells when tested in cytotoxicity assay. In long term cocultures stimulation of purified CD8(+) T cells with matured DC pulsed with PSA peptides generated a PSA-specific CTL response in 4 of 6 patients studied and in 2 of 9 normal donors. While our observations of CTL generation are consistent with the prior reports that have demonstrated that specific CD8(+) CTL could be generated which recognize PSA-derived epitopes by in vitro stimulation by one means or another, this observation that IFN-gamma-producing CD8(+) T cells are present in patients which are antigen experienced, and do not require in vitro stimulation, is novel and has major implications for prostate cancer vaccine preparation.
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PMID:Recognition of PSA-derived peptide antigens by T cells from prostate cancer patients without any prior stimulation. 1278 16

We tried to identify prostate-specific membrane antigen (PSMA)-derived peptides capable of eliciting both cellular and humoral immune responses in peripheral blood mononuclear cells (PBMCs) and plasma of HLA-A24(+) prostate cancer patients, respectively. For cellular response, peptide-specific and prostate cancer-reactive responses of in vitro-stimulated PBMCs were examined with regard to interferon (IFN)-gamma production and cytotoxicity against both a parental HLA-A24(-) prostate cancer cell line (PC-93) and an HLA-A24-expressing transfectant cell line (PC93-A24). For humoral response, patients' plasma was tested for reactivity to the peptides by means of an enzyme-linked immunosorbent assay (ELISA). Among 13 PSMA peptides, PSMA 624-632 peptide induced peptide-specific and tumor-reactive cytotoxic T lymphocytes (CTLs) most effectively. The PSMA 624-632 peptide-stimulated PBMCs from either healthy donors or prostate cancer patients produced a significant level of IFN-gamma in response to prostate cancer cells in an HLA-A24-restricted manner, and also showed a higher level of cytotoxicity against PC93-A24 than against PC93. Antibodies to the PSMA 624-632 peptide, but not to any others, were detected in prostate cancer patients. These results demonstrate that the PSMA 624-632 peptide could be an appropriate molecule for use in specific immunotherapy of HLA-A24(+) patients with prostate cancer.
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PMID:Identification of a prostate-specific membrane antigen-derived peptide capable of eliciting both cellular and humoral immune responses in HLA-A24+ prostate cancer patients. 1284 72

Murine models have shown that IL-18 has antiangiogenic and antitumor effects, but little is known about IL-18 production in human tumors. We investigated IL-18 expression in clinically localized prostate cancers by immunohistochemistry and showed that 75% of the prostate cancers studied (27/36 cases) presented with tumor cells producing IL-18. Prostate tumor cell lines PC-3, DU 145 and LNCaP synthesized the immature form of IL-18 (p24). IFN-gamma produced in prostate cancers induced caspase-1 mRNA and IL-18 secretion of tumor cell lines, which was inhibited by the cell-permeable Tyr-Val-Ala-Asp-aldehyde caspase-1 inhibitor (YVAD-CHO). Interestingly, IFN-alpha also induced IL-18 secretion of the poorly differentiated cell line PC-3. PC-3 and DU 145, but not the well-differentiated cell line LNCaP, expressed IL-18R alpha (IL-1Rrp) protein and transcripts for IL-18R beta (AcPL). Exogenous IL-18 increased mitochondrial activity of both cell lines evaluated by the tetrazolium (MTT) assay but did not influence their proliferation. This indicated that prostate tumor cells could secrete IL-18 in response to IFN-gamma in the tumor microenvironment and that IL-18 could act as a autocrine/paracrine factor for the tumor. In the cohort of patients studied, IL-18 expression in prostate cancers (with up to 10% of tumor cells stained) was associated with a favorable outcome and equally predictive as pathologic stage on multivariate analysis (log rank test, p = 0.02). Tumor IL-18 production is a novel physiopathologic feature of prostate cancer and appears to be a favorable event in the course of the disease. Modulation of IL-18 production by interferons could have a beneficial clinical effect, which deserves further investigation.
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PMID:IL-18 is produced by prostate cancer cells and secreted in response to interferons. 1291 59

HER-2/neu oncoprotein contains several major histocompatibility complex class I-restricted epitopes, which are recognised by cytotoxic T lymphocyte (CTL) on autologous tumours and therefore can be used in immune-based cancer therapies. Of these, the most extensively studied is HER-2(9(369)). In the present report, we used dendritic cells pulsed with HER-2(9(369)) to stimulate, in the presence of IL-7 and IL-12, the production of IFN-gamma by patients' CTL detected by the enzyme-linked immunosorbent spot-assay. Frequencies of peptide-specific precursors were estimated in HLA-A2, HLA-A3 and HLA-A26 patients with HER-2/neu-positive (+) breast, ovarian, lung, colorectal and prostate cancers and healthy individuals. We found increased percentages of such precursors in HLA-A2 (25%) and HLA-A26 (30%) patients, which were significantly higher (60%) in HLA-A3 patients. Our results demonstrate for the first time that pre-existing immunity to HER-2(9(369)) occurs in patients with colorectal, lung and prostate cancer. They also suggest that HER-2(9(369)) can be recognised by CTL, besides HLA-A2, also in the context of HLA-A3 and HLA-A26, thus increasing the applicability of HER-2(9(369))-based vaccinations in a considerably broader patients' population.
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PMID:Cytotoxic T-cell precursor frequencies to HER-2 (369-377) in patients with HER-2/neu-positive epithelial tumours. 1296 25

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.
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PMID:Vaccination of prostatectomized prostate cancer patients in biochemical relapse, with autologous dendritic cells pulsed with recombinant human PSA. 1476 May 10

In order to develop immunotherapies for prostate cancer, many groups are exploring vaccination strategies to induce an immune response against prostate specific antigen (PSA). To determine if T-cell recognition of PSA might be a feature of a naturally occurring human disease, we have studied patients with prostatitis, a poorly understood clinical syndrome of men in which there is evidence that an immune response directed against the prostate may be occurring. We wished to determine if a T-cell response to PSA might be occurring in these patients. We generated long-term T-cell lines from peripheral blood mononuclear cells (PBMC) of one patient with granulomatous prostatitis using purified PSA as an antigen. Several CD4+ and CD8+ TcR alpha/beta+ T-cell lines were selected for PSA reactivity as measured by at least a threefold increase in IFN-gamma secretion in response to PSA presented by irradiated autologous PBMC. CD4 and CD8 T-cell lines recognized PSA in the context of HLA-DRbeta1*1501 and HLA-B*0702, respectively. The specificity and HLA restriction of the lines was confirmed using EBV-B cell lines infected with a recombinant PSA-expressing vaccinia virus and also engineered to express PSA by retroviral transfection. HLA-matched targets infected by control vector as well as HLA-mismatched PSA-expressing targets did not induce the response. The data demonstrate that PSA-specific T cells are present in the PBMC of this patient with granulomatous prostatitis, who may be manifesting naturally the type of immune response directed at the prostate that is the goal of prostate cancer immunotherapy. However, the Class I-restricted epitope has not yet been demonstrated to be expressed on the surface of prostate cancer cells. To our knowledge, this is the first demonstration of HLA-DRB1*1501- or HLA-B*0702-restricted responses to PSA and extends the number of HLA molecules accommodating the use of PSA antigen as a candidate vaccine for prostate cancer immunotherapy.
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PMID:CD4 and CD8 T-lymphocyte recognition of prostate specific antigen in granulomatous prostatitis. 1597 30

Despite the potency with which dendritic cells (DCs) are able to utilize the exogenous MHC I antigen cross-presentation pathway to cross-present antigen for the activation of killer T cells in model systems, concern about defects in immune function in cancer patients has led to uncertainty regarding whether immune cells derived from patients can effectively be used to generate tumor vaccines. We have undertaken a careful analysis of the potency of using DCs obtained from prostate cancer patients to cross-present antigen derived from human prostate tumor cells for the activation of antigen-specific T cells. Such DCs can be matured ex vivo into functionally active cells and are capable of cross-presenting influenza antigen derived from internalized apoptotic prostate tumor cells. Importantly, we demonstrate effective stimulation of both CD4+ and CD8+ T cells, as evident by production of IFN-gamma, and the ability of CD8+ T cells to differentiate into effector CTLs. These results, defining conditions in which prostate cancer patient DCs can efficiently utilize the cross-presentation pathway and in which apoptotic tumor can serve as a source of antigen for DCs to activate T cells, demonstrate that this system warrants clinical study as a potential immunotherapy.
Prostate Cancer Prostatic Dis 2004
PMID:Effective antigen cross-presentation by prostate cancer patients' dendritic cells: implications for prostate cancer immunotherapy. 1499 41

Fusion proteins are emerging as a promising approach for targeting cytokines to the tumor site in order to generate an effective anti-tumor response. In this study, a fusion protein, chTNT-3/huIL-12, consisting of the necrosis targeting antibody, chTNT-3, and human interleukin-12 (IL-12), was constructed and expressed using the glutamine synthetase gene amplification system in NS0 cells. For these studies, IL-12 was chosen since it has been shown to be a powerful anti-tumor cytokine. To generate the fusion protein, an expression vector was prepared by linking the huIL-12 p35 subunit cDNA to the 3' end of the chTNT-3 heavy chain cDNA and the p40 subunit was added to a separate vector. The activity of the expressed chTNT-3/huIL-12 was confirmed by standard IL-12 bioactivity assays which demonstrated that the fusion protein induced similar levels of peripheral blood lymphocyte (PBL) proliferation as free recombinant IL-12. In addition, the lytic activity of the fusion protein was demonstrated in both naive and IL-2-activated lymphocytes using cytotoxicity assays against three human pancreatic and prostatic cancer cell lines (CAPAN, DU145, and PC3-MA). Human PBL incubated with this fusion protein showed an increase in IFN-gamma production which was augmented dramatically by pre-incubation with IL-2. Finally, the immunotherapeutic potential of the fusion protein was demonstrated in the human PBL-SCID mouse model where a 44% reduction in DU145 prostatic tumor growth was obtained compared to control treated mice. These results demonstrate that tumor-targeted human IL-12 may be an effective immunotherapeutic reagent for the treatment of solid tumors in man.
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PMID:chTNT-3/hu IL-12 fusion protein for the immunotherapy of experimental solid tumors. 1500 Aug 42

HER2/neu is a proto-oncogene and a member of the epidermal growth factor receptor family of proteins that is overexpressed in numerous types of human cancer. We are currently conducting clinical trials with the HER2/neu E75 peptide vaccine in breast and prostate cancer patients. We have evaluated the use of HLA-A2 dimer molecule for the immunological monitoring of cancer patients receiving the E75 peptide vaccine. Peripheral blood samples from patients receiving the vaccine were stained with HLA-A2 dimers containing the vaccine peptide E75 or control peptides and analyzed by flow cytometry. We compared the HLA-A2 dimer assay to standard methods of immunologic monitoring (IFN-gamma release, lymphocyte proliferation, and cytotoxicity). The HLA-A2 dimer assay was also compared with the HLA-A2 tetramer assay. E75 peptide-specific CD8 T cells were detected directly in the peripheral blood of patients by staining with E75-HLA-A2 dimers and CD8 antibodies. T cell cultures generated by repeated stimulations using E75 peptide-pulsed dendritic cells showed increased staining with E75-peptide loaded HLA-A2 dimers. Simultaneously analysis by the dimer assay and standard immunologic assays demonstrated that the dimer-staining assay correlated well with these methods of immunologic monitoring. A direct comparison using E75-specific HLA-A2 tetramers and HLA-A2 dimers for the detection of E75-specific CD8 T cells in peripheral blood showed comparable results with the two assays. Our findings indicate that the HLA-A2 dimer is a powerful new tool for directly quantifying and monitoring immune responses of antigen-specific T cells in peptide vaccine clinical trials.
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PMID:Direct measurement of peptide-specific CD8+ T cells using HLA-A2:Ig dimer for monitoring the in vivo immune response to a HER2/neu vaccine in breast and prostate cancer patients. 1516 2

Prostate-specific antigen (PSA) is a serine protease secreted at low levels by normal luminal epithelial cells of the prostate and in significantly higher levels by prostate cancer cells. Therefore, PSA is a potential target for various immunotherapeutical approaches against prostate cancer. DNA vaccination has been investigated as immunotherapy for infectious diseases in patients and for specific treatment of cancer in certain animal models. In animal studies, we have demonstrated that vaccination with plasmid vector pVAX/PSA results in PSA-specific cellular response and protection against tumour challenge. The purpose of the trial was to evaluate the safety, feasibility and biological efficacy of pVAX/PSA vaccine in the clinic. A phase I trial of pVAX/PSA, together with cytokine granulocyte/macrophage-colony stimulating factor (GM-CSF) (Molgramostim) and IL-2 (Aldesleukin) as vaccine adjuvants, was carried out in patients with hormone-refractory prostate cancer. To evaluate the biologically active dose, the vaccine was administered during five cycles in doses of 100, 300 and 900 microg, with three patients in each cohort. Eight patients were evaluable. A PSA-specific cellular immune response, measured by IFN-gamma production against recombinant PSA protein, and a rise in anti-PSA IgG were detected in two of three patients after vaccination in the highest dose cohort. A decrease in the slope of PSA was observed in the two patients exhibiting IFN-gamma production to PSA. No adverse effects (WHO grade >2) were observed in any dose cohort. We demonstrate that DNA vaccination with a PSA-coding plasmid vector, given with GM-CSF and IL-2 to patients with prostate cancer, is safe and in doses of 900 microg the vaccine can induce cellular and humoral immune responses against PSA protein.
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PMID:A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer. 1528 Sep 30


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