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)

SART3-derived peptides applicable to prostate cancer patients with HLA-A3 supertype alleles were identified in order to expand the possibility of an anti-cancer vaccine, because the peptide vaccine candidates receiving the most attention thus far have been the HLA-A2 and HLA-A24 alleles. Twenty-nine SART3-derived peptides that were prepared based on the binding motif to the HLA-A3 supertype alleles (HLA-A11, -A31, and -A33) were first screened for their recognizability by immunoglobulin G (IgG) of prostate cancer patients and subsequently for the potential to induce peptide-specific cytotoxic T lymphocytes (CTLs) from HLA-A3 supertype(+) prostate cancer patients. As a result, five SART3 peptides were frequently recognized by IgG, and two of them-SART3 (511-519) and SART3 (734-742)-efficiently induced peptide-specific and cancer-reactive CTLs. Their cytotoxicity toward prostate cancer cells was ascribed to peptide-specific and CD8(+) T cells. These results indicate that these two SART3 peptides could be promising candidates for peptide-based immunotherapy for HLA-A3 supertype(+) prostate cancer patients.
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PMID:Identification of SART3-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from prostate cancer patients with HLA-A3 supertype alleles. 1693 15

Prostate stem cell antigen (PSCA) and prostate-specific antigen (PSA) are overexpressed in most prostate cancers. PSCA- and PSA-derived, HLA-A2 binding peptides are specific targets for T-cell responses in vitro. A phase I/II trial was performed to demonstrate feasibility, safety and induction of antigen-specific immunity by vaccination with dendritic cells (DC) presenting PSCA and PSA peptides in patients with hormone- and chemotherapy-refractory prostate cancer. Patients received 4 vaccinations with a median of 2.7 x 10(7) peptide-loaded mature DC s.c. in biweekly intervals. Clinical responses were assessed 2 weeks after the 4th vaccination. Immune monitoring was performed by DTH and HLA multimer analysis. Twelve patients completed vaccination without relevant toxicities. Six patients had stable disease after 4 vaccinations. One patient had a complete disappearance of lymphadenopathy despite rising PSA. Four patients with SD and 1 progressor developed a positive DTH after the 4th vaccination. With a median survival of all patients of 13.4 months, DTH-positivity was associated with significantly superior survival (p = 0.003). HLA tetramer analysis detected high frequencies of peptide-specific T cells after 2 vaccinations in 1 patient who was also the sole responder to concomitant hepatitis B vaccination as an indicator of immune competence and survived 27 months after start of vaccination. Vaccination with PSA/PSCA peptide-loaded, autologous DCs may induce cellular responses primarily in immunocompetent patients, which appear to be associated with clinical benefit. Testing of DC-based vaccination is warranted for patients at earlier stages of prostate cancer.
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PMID:Vaccination of advanced prostate cancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTH responses that correlate with superior overall survival. 1697 30

Immunological treatment of cancer has made some very promising advances during the last years. Anti-cancer vaccination using peptides or peptide-pulsed dendritic cells and adoptive transfer of in vitro generated, epitope-specific T cells depend on a well-fitting interaction of HLA molecule and epitope. Accurate HLA-typing is a key factor for successful anti-cancer vaccination. No comprehensive data and no suggestion exist on the HLA-typing in this setting. We performed a systematic review of PubMed analyzing HLA-typing data in cancer vaccination trials over the last 4 years (2004-2007). Then, using the SYFPEITHI database, we calculated the peptide binding prediction of the eight most often used HLA-A*0201 binding epitopes. Finally, high-resolution typing [by sequence-specific primers (SSP)] data of a HLA-A*02 or HLA-A*24 positive population in Berlin, Germany, were analyzed. Forty-five cancer vaccination trials with 764 patients were included. Eighteen studies were performed in the USA, 13 in Europe, 12 in Asia (mainly Japan), and two in Australia. Most common diseases targeted were melanoma, prostate cancer, colorectal cancer, renal cell cancer, and breast cancer. The trials tested protocols using peptide plus adjuvants without DC or protocols using peptide-pulsed DC. In 38 trials (84%) HLA-A2 positive patients were vaccinated, in 11 studies (24%) HLA-A24 positive patients were vaccinated. Nineteen studies with 291 patients (38%) presented the HLA type as four-digit code (high-resolution), 26 studies with 473 patients (62%) presented the HLA-type in a low-resolution code. The method of HLA determination was given in six out of 45 trials (13%). Using the SYFPEITHI database we calculated the peptide binding prediction of the eight most often used HLA-A*0201 binding tumor antigen-derived epitopes for binding to HLA-A*0203. While the epitopes had a binding score of 17-28 for HLA-A*0201, the score for binding to HLA-A*0203 was zero in seven out of eight tested peptides. Only for one peptide the score was eight. Finally, we analyzed high-resolution data of HLA-A*02 and HLA-A*24 positive patients in Berlin, Germany. We found the HLA-A*0201 allele and HLA-A*2402 allele in 95%, respectively. HLA-A*0201 and HLA-A*2402 are most commonly used for peptide based vaccine in cancer. Data on HLA-typing given in the included cancer vaccine manuscripts are fractional. Only 13% report the method of HLA typing and most HLA types are given as low-resolution code. Looking at the binding of specific peptides to both the alleles, it is important to perform high-resolution typing. Further suggestions for immunogenetic laboratories and clinical tumor immunologists regarding HLA-typing for cancer vaccine trials and adoptive T cell transfer approaches are discussed.
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PMID:HLA typing demands for peptide-based anti-cancer vaccine. 1831 54

Clinical trials are governed by an increasingly stringent regulatory framework, which applies to all levels of trial conduct. Study critical immunological endpoints, which define success or failure in early phase clinical immunological trials, require formal pre-trial validation. In this case study, we describe the assay validation process, during which the sensitivity, and precision of immunological endpoint assays were defined. The purpose was the evaluation of two multicentre phase I/II clinical trials from our unit in Southampton, UK, which assess the effects of DNA fusion vaccines on immune responses in HLA-A2+ patients with carcinoembryonic antigen (CEA)-expressing malignancies and prostate cancer. Validated immunomonitoring is being performed using ELISA and IFNgamma ELISPOTs to assess humoral and cellular responses to the vaccines over time. The validated primary endpoint assay, a peptide-specific CD8+ IFNgamma ELISPOT, was tested in a pre-trial study and found to be suitable for the detection of low frequency naturally occurring CEA- and prostate-derived tumour-antigen-specific T cells in patients with CEA-expressing malignancies and prostate cancer.
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PMID:Fit for purpose? A case study: validation of immunological endpoint assays for the detection of cellular and humoral responses to anti-tumour DNA fusion vaccines. 1906 88

We previously reported the SART3 gene to be a tumor-rejection antigen gene encoding a peptide at positions 109-118 (SART3(109-118)) with the ability to induce HLA-A24-restricted cytotoxic T lymphocytes. In this study, we investigated both humoral and cellular responses to this peptide in cancer patients with alleles other than HLA-A24 to explore the possibility of using this peptide as a cancer vaccine for these patients. IgG reactive to SART3(109-118) peptide was identified in sera of the vast majority of non-cancer subjects (n=50) and all cancer patients (n=50) tested without apparent HLA-A association. Levels of anti-SART3(109-118) peptide antibody in cancer patients were significantly higher than those of non-cancer subjects, but no difference was found between HLA-A24+A2- and HLA-A24-A2+ cancer patients. This peptide induced cancer cell-reactive cytotoxic T lymphocytes from peripheral blood mononuclear cells of both healthy donors and prostate cancer patients with HLA-A11, HLA-A31 and HLA-A33 alleles, but not with HLA-A2. These results suggest that this peptide can be applicable as a cancer vaccine not only for HLA-A24+, but also for HLA-A11+, HLA-A31+ and HLA-A33+ prostate cancer patients.
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PMID:Capability of SART3(109-118) peptide to induce cytotoxic T lymphocytes from prostate cancer patients with HLA class I-A11, -A31 and -A33 alleles. 1914 89

Efficacy of vaccination in cancer patients on immunotherapeutic protocols can be difficult to evaluate. The aim of this study was therefore to identify a single natural or modified epitope in prostate-specific antigen (PSA) with the ability to generate high levels of PSA-specific T cells to facilitate monitoring in patients after vaccination against prostate cancer. To the best of our knowledge, this study describes for the first time the peptide specificity of T cells stimulated by endogenously processed PSA antigen. The peptide specificity of HLA-A*0201-restricted CD8(+) T cells against human and rhesus PSA was investigated both in vivo after DNA vaccination in HLA-A*0201-transgenic mice and in vitro after repetitive stimulation of human T cells with DNA-transfected human dendritic cells (DCs). One of seven native PSA peptides, psa53-61, was able to activate high levels of PSA-specific CD8(+) T cells in HLA-A*0201-transgenic mice after PSA DNA vaccination. Psa53-61 was also the only peptide that induced human T cells to produce IFNgamma after stimulation with PSA transfected DCs, however not in all donors. Therefore, plasmids encoding modified epitopes in predicted HLA-A*0201 sequences were constructed. One of these modified PSA plasmids consistently induced IFNgamma producing CD8(+) T cells to the corresponding modified peptide as well as to the corresponding native peptide, in all murine and human T cell cultures. This study demonstrates a novel concept of introducing a modified epitope within a self-tumor antigen, with the purpose of eliciting a reliable T cell response from the non-tolerized immune repertoire, to facilitate monitoring of vaccine efficacy in cancer patients on immunotherapeutic protocols. The purpose of such a modified epitope is thus not to induce therapeutically relevant T cells but rather to, in case of weak or divergent T cell responses to self antigens/peptides, help answer questions about efficacy of vaccine delivery and about the possibility to induce immune responses in the selected and often immunosuppressed cancer patients.
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PMID:A modified epitope identified for generation and monitoring of PSA-specific T cells in patients on early phases of PSA-based immunotherapeutic protocols. 1917 Nov 73

We previously reported peptide vaccine candidates for HLA-A3 supertype (-A3, -A11, -A31, -A33)-positive cancer patients. In the present study, we examined whether those peptides can also induce cytotoxic T lymphocyte (CTL) activity restricted to HLA-A2, HLA-A24, and HLA-A26 alleles. Fourteen peptides were screened for their binding activity to HLA-A*0201, -A*0206, -A*0207, -A*2402, and -A*2601 molecules and then tested for their ability to induce CTL activity in peripheral blood mononuclear cells (PBMCs) from prostate cancer patients. Among these peptides, one from the prostate acid phosphatase protein exhibited binding activity to HLA-A*0201, -A*0206, and -A*2402 molecules. In addition, PBMCs stimulated with this peptide showed that HLA-A2 or HLA-A24 restricted CTL activity. Their cytotoxicity toward cancer cells was ascribed to peptide-specific and CD8+ T cells. These results suggest that this peptide could be widely applicable as a peptide vaccine for HLA-A3 supertype-, HLA-A2-, and -A24-positive cancer patients.
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PMID:An HLA-A3-binding prostate acid phosphatase-derived peptide can induce CTLs restricted to HLA-A2 and -A24 alleles. 1933 Mar 28

Immunotherapy with whole cell cancer vaccines has been tested in various tumor types. This study investigated the safety profile and antitumor activity of an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant human interleukin-2 and human interferon-gamma. Thirty HLA-A*0201-matched patients with progressive, castration-resistant prostate cancer received four intradermal injections on days 1, 15, 29, and 92, and then every 90 days, as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, and 27 patients received 15 million cells per injection. The primary study criteria were safety and the difference in prostate-specific antigen doubling time (PSA-DT), determined in the pretreatment phase (before the start of vaccination) and in the trial treatment phase (during vaccination). No dose-limiting or autoimmune toxicity was seen. During vaccination there was a significant prolongation of the PSA-DT compared with the prevaccination period (prolongation from 63 to 114 days; p < 0.01; intention to treat). In addition, results showed a period of PSA stabilization of at least 12 weeks, together with stable bone scans in 12 of 30 patients, and 3 patients sustained a >50% decrease in PSA versus baseline. The median overall survival time from first vaccination was 32 months (mean value, 34 months). Immune monitoring revealed T cell stimulation in the majority of patients. This vaccine strategy was found to be safe and well tolerated and was accompanied by prolongation of PSA-DT. The results of this trial warrant clinical development of this vaccine.
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PMID:Therapeutic vaccination with an interleukin-2-interferon-gamma-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial. 1967 Oct

One-fifth of the Japanese population is positive for HLA-A26, but few peptides are available as potential cancer vaccines for HLA-A26-positive cancer patients. The objective of this study was to identify peptide vaccine candidates for HLA-A26-positive cancer patients. The HLA-A*2601-crossbinding activity of 24 peptides currently under clinical trial as vaccines for HLA-A2, -A24, or HLA-A3 supertype-positive cancer patients was evaluated by stabilization assay. Three peptides with HLA-A2-binding activity could bind the HLA-A*2601 molecule. These three peptides induced HLA-A26-restricted cytotoxic T lymphocytes from HLA-A*2601-, -A*2602-, or -A*2603-positive prostate cancer patients against HLA-A*2601- and HLA-A*2603-positive cancer cells in CD8-dependent and peptide-specific manners. In addition, one peptide with HLA-A24-binding activity could bind to HLA-A*2601 and induced HLA-A26-restricted cytotoxic T lymphocytes from HLA-A*2601-, -A*2602-, or -A*2603-positive prostate cancer patients against HLA-A*2603-positive cancer cells. These results may provide novel information for the development of a peptide-based cancer vaccine for HLA-A26-positive patients.
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PMID:Identification of peptides applicable as vaccines for HLA-A26-positive cancer patients. 1968 76

Antisense oligonucleotides have been employed against in vivo and in vitro prostate cancer models. While most oligos consist of a single mRNA binding site, targeting a single gene product or others sharing sequence homology, our laboratory has developed bispecific oligos directed toward even unrelated proteins. This study evaluates the inhibition of in vitro propagating LNCaP cells employing mono- and bispecific oligos directed against bcl-2 [the second bispecific binding site was directed against the epidermal growth factor receptor (EGFR)]. Employing RT-PCR, the expression of non-targeted proteins encoded by mRNA for prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were subsequently evaluated. When LNCaP prostate tumor cells were incubated with bispecific oligos (directed against bcl-2 and EGFR) and compared to lipofectin-containing controls significant growth inhibition resulted. In subsequent experiments, the levels of mRNA encoding PSMA were unexpectedly found to be elevated following treatment with the bispecific oligos but not with the monospecific directed solely against bcl-2. No differences were detected in mRNA levels encoding PSA following treatment with either mono- or bispecific oligos. Previously, we suggested that cell growth inhibition produced by some bispecifics could be attributed to complementary double-stranded regions formed by intra-strand base pairs. Double-stranded nucleic acids are known inducers of interferon, which promote expression of cell surface HLA type antigens. If induced, perhaps this cytokine also enhances PSMA expression, making prostate tumor cells a more recognizable target for cytotoxic T cells.
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PMID:Increased prostate-specific membrane antigen expression in LNCaP cells following treatment with bispecific antisense oligonucleotides directed against bcl-2 and EGFR. 1993 63


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