Prostate Cancer Research

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Preventive and therapeutic vaccination with PAP-3, a novel human prostate cancer peptide, inhibits carcinoma development in HLA transgenic mice.

Cancer Immunol Immunother. 2007 Feb;56(2):217-26

Authors: Machlenkin A, Azriel-Rosenfeld R, Volovitz I, Vadai E, Lev A, Paz A, Goldberger O, Reiter Y, Tzehoval E, Benhar I, Eisenbach L

Conventional treatment of recurrent and metastasized prostate cancer (CaP) remains inadequate; this fact mandates development of alternative therapeutic modalities, such as specific active or passive immunotherapy. Previously, we reported the identification of a novel highly immunogenic HLA-A*0201-restricted Prostatic Acid Phosphatase-derived peptide (PAP-3) by a two-step in vivo screening in an HLA-transgenic (HHD) mouse system. In the present study we aimed at elucidating the efficiency of PAP-3-based vaccine upon active antitumor immunization. To this end we established preventive and therapeutic carcinoma models in HHD mice. The 3LL murine Lewis lung carcinoma clone D122 transduced to express HLA-A*0201 and PAP served as a platform for these models. The HLA-A*0201-PAP-3 complex specific recombinant single chain scFV-PAP-3 antibodies were generated and used to confirm an endogenous PAP processing resulting in PAP-3 presentation by HLA-A*0201. PAP-3 based vaccines significantly decreased tumor incidence in a preventive immunization setting. Therapeutic vaccination of HHD mice with PAP-3 led to rejection of early established tumors and to increase of mouse survival. These results strongly support a therapeutic relevance of the identified CTL epitope upon active antitumor immunization. The newly established carcinoma model presented herein might be a useful tool for cancer vaccine design and optimization.

PMID: 16738849 [PubMed - indexed for MEDLINE]

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The Second International Meeting on Allogeneic Transplantation in Solid Tumors.

Bone Marrow Transplant. 2006 Sep 4;

Authors: Bregni M, Ueno NT, Childs R

In October 2005, the second international meeting on allogeneic transplantation in solid tumors was convened in Stresa (Italy). The aim of this second meeting was to share clinical experiences of allografting in solid tumors, to discuss preclinical data on the mechanisms of graft-versus-tumor (GVT) effect, and to review methods for more efficacious transplant approaches. On the first day, the most recent results in cancer immunotherapy were reviewed; head-to head comparisons of clinical results achieved by standard therapy and by allografting in renal, breast, and ovarian cancer were presented. On the second day, GVT mechanisms and preclinical models were examined; anecdotal reports of a GVT effect in sarcoma, pancreatic cancer, prostate cancer, colorectal cancer and lung cancer were presented; new strategies for optimizing transplant outcome were discussed, including patient selection, tumor debulking, auto-allo approaches, selective T-cell depletion, targeting with monoclonal antibodies, use of killer cell immunoglobulin-like receptor-ligand mismatched natural killer cells. In conclusion, allografting in solid tumors is feasible with limited toxicities and transplant-related mortality; a GVT effect has been documented in many different solid tumors; targeting of the immune response to the tumor by new strategies and identification of the target antigen(s) of the GVT effect are promising areas of research.Bone Marrow Transplantation advance online publication, 4 September 2006; doi:10.1038/sj.bmt.1705479.

PMID: 16953213 [PubMed - as supplied by publisher]

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Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy.

Cancer. 2006 Jul 1;107(1):67-74

Authors: Rini BI, Weinberg V, Fong L, Conry S, Hershberg RM, Small EJ

BACKGROUND: APC8015 (sipuleucel-T) is a cellular prostate cancer vaccine containing autologous antigen-presenting cells (APC) loaded with PA2024, a recombinant prostatic acid phosphatase/granulocyte-macrophage-colony-stimulating factor fusion protein, as the immunogen. Bevacizumab is a recombinant antibody against vascular endothelial growth factor, a proangiogenic protein with inhibitory effects on APC. A clinical trial was conducted to determine the prostate-specific antigen (PSA) and immunomodulatory effects of this combination immunotherapy. METHODS: Patients with androgen-dependent prostate cancer who had received prior definitive therapy with nonmetastatic, recurrent disease as manifested by a rising PSA of between 0.4 ng/mL and 6.0 ng/mL were enrolled. APC8015 was given intravenously(i.v.) on Weeks 0, 2, and 4. Bevacizumab was given at a dose of 10 mg/kg i.v. on Weeks 0, 2, 4, and every 2 weeks thereafter until toxicity or disease progression. PSA changes were recorded and the PSA doubling time (PSADT) was calculated. Immune response versus PA2024 was measured at baseline and after treatment by T-cell proliferation and interferon-gamma enzyme-linked immunospot (ELISPOT) assays. RESULTS: Twenty-two patients were treated. One patient achieved a > or =50% decrease in PSA. Nine patients exhibited some decrease in PSA from baseline, ranging from 6% to 72%, with the PSA of 3 patients decreasing at least 25%. The median pretreatment PSADT for the 20 evaluable patients was 6.9 months and the median posttreatment PSADT was 12.7 months (P = .01). All patients demonstrated induction of an immune response against PA2024. CONCLUSIONS: The combination of APC8015 and bevacizumab induces an immune response and modulates PSA in patients with biochemically recurrent prostate cancer.

PMID: 16736512 [PubMed - indexed for MEDLINE]

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Nitroreductase-based therapy of prostate cancer, enhanced by raising expression of heat shock protein 70, acts through increased anti-tumour immunity.

Cancer Immunol Immunother. 2006 Mar;55(3):347-54

Authors: Lipinski KS, Pelech S, Mountain A, Irvine AS, Kraaij R, Bangma CH, Mills KH, Todryk SM

Gene-directed enzyme-prodrug therapy (GDEPT) using nitroreductase (NTR), with efficient adenoviral delivery, and CB1954 (CB), is an effective means of directly killing tumours. However, an immune-mediated bystander effect remains an important product of GDEPT since it is often critical to the elimination of untransduced tumour cells both locally and at distal metastatic sites through generation of tumour-specific immunity without the need for tumour antigen identification or the generation of a personalised vaccine. The mode of induced tumour cell death is thought to contribute to the immunisation process, together with the induction and release of stress proteins. Here, RM-9 murine prostate tumour cells were efficiently killed by adenovirally delivered NTR/CB treatment both in vitro and in vivo, and bystander effects were observed. Cells appeared to die by pathways that suggest necrosis more than that of classical apoptosis. NTR/CB-induced expression of a range of stress proteins was determined by proteomic analysis, revealing chiefly heat shock protein (HSP)25 and HSP70 upregulation, whilst immune responses in vivo were weak. In an attempt to enhance the anti-tumour effect, an adenoviral vector was constructed that co-expressed NTR and HSP70, the latter being a known immune stimulator and chaperone of antigen. This combination elicited significantly enhanced protection over NTR alone for both the treated tumour and a subsequent re-challenge. Protection was CD4+ and CD8+ T cell-dependent and was associated with tumour-specific CTL, IFNgamma and IL-5 responses. The use of such a cytotoxic and immunomodulatory gene combination in cancer therapy warrants further pursuit.

PMID: 16075195 [PubMed - indexed for MEDLINE]

Posted by at 12:43 PM | Permalink

[Cancer immunotherapy--current status]

Ther Umsch. 2006 Apr;63(4):262-6

Authors: Kundig TM, Renner Ch, Knuth A

Cancer immunotherapy includes passive and active strategies. Passive immunotherapy such as the use of therapeutic monoclonal antibodies, and in a broader sense also of other immunological effector molecules, such as interferon-alpha is clinically established. The efficacy of passive immunotherapy attests to the fact that the immune system can successfully fight cancer. The logical next step is therefore to develop strategies for active immunotherapy, i.e. "vaccines against cancer". This review focuses on the current status of active immunotherapy with respect to clinical application. Although active immunotherapy is still in the experimental stage, the data are highly encouraging and it is expected that vaccination will soon become part of cancer management.

PMID: 16689457 [PubMed - indexed for MEDLINE]

Posted by at 8:56 PM | Permalink

Related Articles

Preventive and therapeutic vaccination with PAP-3, a novel human prostate cancer peptide, inhibits carcinoma development in HLA transgenic mice.

Cancer Immunol Immunother. 2006 Jun 1;

Authors: Machlenkin A, Azriel-Rosenfeld R, Volovitz I, Vadai E, Lev A, Paz A, Goldberger O, Reiter Y, Tzehoval E, Benhar I, Eisenbach L

Conventional treatment of recurrent and metastasized prostate cancer (CaP) remains inadequate; this fact mandates development of alternative therapeutic modalities, such as specific active or passive immunotherapy. Previously, we reported the identification of a novel highly immunogenic HLA-A*0201-restricted Prostatic Acid Phosphatase-derived peptide (PAP-3) by a two-step in vivo screening in an HLA-transgenic (HHD) mouse system. In the present study we aimed at elucidating the efficiency of PAP-3-based vaccine upon active antitumor immunization. To this end we established preventive and therapeutic carcinoma models in HHD mice. The 3LL murine Lewis lung carcinoma clone D122 transduced to express HLA-A*0201 and PAP served as a platform for these models. The HLA-A*0201-PAP-3 complex specific recombinant single chain scFV-PAP-3 antibodies were generated and used to confirm an endogenous PAP processing resulting in PAP-3 presentation by HLA-A*0201. PAP-3 based vaccines significantly decreased tumor incidence in a preventive immunization setting. Therapeutic vaccination of HHD mice with PAP-3 led to rejection of early established tumors and to increase of mouse survival. These results strongly support a therapeutic relevance of the identified CTL epitope upon active antitumor immunization. The newly established carcinoma model presented herein might be a useful tool for cancer vaccine design and optimization.

PMID: 16738849 [PubMed - as supplied by publisher]

Posted by at 3:44 PM | Permalink

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Association of prostate-specific membrane antigen with caveolin-1 and its caveolae-dependent internalization in microvascular endothelial cells: Implications for targeting to tumor vasculature.

Microvasc Res. 2006 May 17;

Authors: Anilkumar G, Barwe SP, Christiansen JJ, Rajasekaran SA, Kohn DB, Rajasekaran AK

Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a highly restricted profile of expression. Expression is primarily limited to secretory cells of the prostatic epithelium, with elevated levels observed in prostate cancer. As an integral membrane protein correlated with prostate cancer, PSMA offers a potentially valuable target for immunotherapy. PSMA is also detected in the neovasculature of a variety of solid tumors but not in the endothelial cells of preexisting blood vessels. Although the significance of PSMA expression in these cells remains elusive, this pattern of expression implies that PSMA may perform a functional role in angiogenesis and may offer a therapeutic target for the treatment of a broad spectrum of solid tumors. In this study, we have expressed PSMA in human microvascular endothelial cells and demonstrate that PSMA binds to caveolin-1 and undergoes internalization via a caveolae-dependent mechanism. The association between PSMA and caveolae in endothelial cells may provide important insight into PSMA function and ways to best exploit this protein for therapeutic benefit.

PMID: 16713605 [PubMed - as supplied by publisher]

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[Neoplastic pathology of the prostate: perspectives]

Pathologica. 2005 Aug;97(4):165-6

Authors: Di Carlo E

PMID: 16440631 [PubMed - indexed for MEDLINE]

Posted by at 8:49 PM | Permalink

[Neoplastic pathology of the prostate: perspectives]

Pathologica. 2005 Aug;97(4):165-6

Authors: Di Carlo E

PMID: 16440631 [PubMed - indexed for MEDLINE]

Posted by at 4:16 PM | Permalink

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STEAP, a prostate tumor antigen, is a target of human CD8(+) T cells.

Cancer Immunol Immunother. 2006 Apr 19;

Authors: Alves PM, Faure O, Graff-Dubois S, Cornet S, Bolonakis I, Gross DA, Miconnet I, Chouaib S, Fizazi K, Soria JC, Lemonnier FA, Kosmatopoulos K

STEAP is a recently identified protein shown to be particularly overexpressed in prostate cancer and also present in numerous human cancer cell lines from prostate, pancreas, colon, breast, testicular, cervical, bladder and ovarian carcinoma, acute lymphocytic leukemia and Ewing sarcoma. This expression profile renders STEAP an appealing candidate for broad cancer immunotherapy. In order to investigate if STEAP is a tumor antigen that can be targeted by specific CD8(+) T cells, we identified two high affinity HLA-A*0201 restricted peptides (STEAP(86-94) and STEAP(262-270)). These peptides were immunogenic in vivo in HLA-A*0201 transgenic HHD mice. Peptide specific murine CD8 T cells recognized COS-7 cells co-transfected with HHD (HLA-A*0201) and STEAP cDNA constructs and also HLA-A*0201(+) STEAP(+) human tumor cells. Furthermore, STEAP(86-94) and STEAP(262-270) stimulated specific CD8(+) T cells from HLA-A*0201(+) healthy donors, and these peptide specific CD8(+) T cells recognized STEAP positive human tumor cells in an HLA-A*0201-restricted manner. Importantly, STEAP(86-94)-specific T cells were detected and reactive in the peripheral blood mononuclear cells in NSCLC and prostate cancer patients ex vivo. These results show that STEAP can be a target of anti-tumor CD8(+) T cells and that STEAP peptides can be used for a broad-spectrum-tumor immunotherapy.

PMID: 16622681 [PubMed - as supplied by publisher]

Posted by at 11:41 AM | Permalink

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STEAP, a prostate tumor antigen, is a target of human CD8(+) T cells.

Cancer Immunol Immunother. 2006 Apr 19;

Authors: Alves PM, Faure O, Graff-Dubois S, Cornet S, Bolonakis I, Gross DA, Miconnet I, Chouaib S, Fizazi K, Soria JC, Lemonnier FA, Kosmatopoulos K

STEAP is a recently identified protein shown to be particularly overexpressed in prostate cancer and also present in numerous human cancer cell lines from prostate, pancreas, colon, breast, testicular, cervical, bladder and ovarian carcinoma, acute lymphocytic leukemia and Ewing sarcoma. This expression profile renders STEAP an appealing candidate for broad cancer immunotherapy. In order to investigate if STEAP is a tumor antigen that can be targeted by specific CD8(+) T cells, we identified two high affinity HLA-A*0201 restricted peptides (STEAP(86-94) and STEAP(262-270)). These peptides were immunogenic in vivo in HLA-A*0201 transgenic HHD mice. Peptide specific murine CD8 T cells recognized COS-7 cells co-transfected with HHD (HLA-A*0201) and STEAP cDNA constructs and also HLA-A*0201(+) STEAP(+) human tumor cells. Furthermore, STEAP(86-94) and STEAP(262-270) stimulated specific CD8(+) T cells from HLA-A*0201(+) healthy donors, and these peptide specific CD8(+) T cells recognized STEAP positive human tumor cells in an HLA-A*0201-restricted manner. Importantly, STEAP(86-94)-specific T cells were detected and reactive in the peripheral blood mononuclear cells in NSCLC and prostate cancer patients ex vivo. These results show that STEAP can be a target of anti-tumor CD8(+) T cells and that STEAP peptides can be used for a broad-spectrum-tumor immunotherapy.

PMID: 16622681 [PubMed - as supplied by publisher]

Posted by at 4:32 PM | Permalink

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Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma.

Cancer Immunol Immunother. 2006 Apr 13;

Authors: Waeckerle-Men Y, Uetz-von Allmen E, Fopp M, von Moos R, B hme C, Schmid HP, Ackermann D, Cerny T, Ludewig B, Groettrup M, Gillessen S

Background: Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer. Patients and methods: Autologous DC of HLA-A*0201(+) patients with hormone-refractory prostate cancer were loaded with antigenic peptides derived from prostate stem cell antigen (PSCA(14-22)), prostatic acid phosphatase (PAP(299-307)), prostate-specific membrane antigen (PSMA(4-12)), and prostate-specific antigen (PSA(154-163)). DC were intradermally applied six times at biweekly intervals followed-in the case of an enhanced immune response-by monthly booster injections. Immune monitoring during the time of ongoing vaccinations (12-59 weeks) included ex vivo ELISPOT measurements, MHC tetramer analysis and in vitro cytotoxicity assays. Results: Of the initial six patients, three qualified for long-term multi-epitope DC vaccination. This regime was tolerated well by all three patients. The vaccination elicited significant cytotoxic T cell responses against all prostate-specific antigens tested. In addition, memory T cell responses against the control peptides derived from influenza matrix protein and tetanus toxoid were efficiently boosted. Clinically, the long-term DC vaccination was associated with an increase in PSA doubling time. Conclusions: DC-based multi-epitope immunotherapy with repeated boosting in men with hormone-refractory prostate carcinoma is feasible and generates efficient cellular antitumor responses.

PMID: 16612599 [PubMed - as supplied by publisher]

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Reevaluation of the 22-1-1 antibody and its putative antigen, EBAG9/RCAS1, as a tumor marker.

BMC Cancer. 2005;5(1):47

Authors: Reimer TA, Anagnostopoulos I, Erdmann B, Lehmann I, Stein H, Daniel P, D rken B, Rehm A

BACKGROUND: Tumor-associated antigens are appreciated as diagnostic markers, but they have also prompted tremendous efforts to develop tumor-specific immunotherapy. A previously cloned tumor-associated antigen, EBAG9, was initially defined by reactivity with the monoclonal antibody 22-1-1. Functionally, the EBAG9-encoded gene-product was believed to induce apoptosis in activated immune cells. However, using a cell-biological approach we identified EBAG9 as a Golgi-resident modulator of O-linked glycan expression, the latter product was then recognized by the 22-1-1 antibody. Secondly, EBAG9 expression was found physiologically in all murine tissues examined. This raised the question if EBAG9 is tumor-specific and mediates apoptosis itself or through O-linked glycans generated, among them the cognate 22-1-1 antigen Tn. METHODS: We have used immunohistochemistry to detect the expression of 22-1-1 and EBAG9 in various tissues. Correlation between expression of both antigens in cell lines was analysed by immunoblot and flow cytometry. Apoptosis was studied by using flow cytometry and Caspase-Glo 3/7 assay kit. Cellular distribution of EBAG9 was analysed by electron and confocal microscopy. RESULTS: Here, we compared expression of the 22-1-1 and EBAG9-defined antigens in normal and neoplastic tissues in situ. In contrast to 22-1-1 staining, EBAG9 is a ubiquitously expressed antigen in all normal and cancerous tissues. Functional studies on the role of 22-1-1 reactive material did not support any evidence for apoptosis induction. Employing electron and confocal microscopy, a refined subcellular localization of EBAG9 at the Golgi was obtained. CONCLUSION: We suggest that the estrogen-inducible EBAG9 gene-product and the 22-1-1 defined antigen are structurally and functionally separate antigens.

PMID: 15904507 [PubMed - indexed for MEDLINE]

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