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]

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[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]

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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]

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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]

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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]

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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]

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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]

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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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Tumor escape mechanisms in prostate cancer.

Cancer Immunol Immunother. 2005 Dec 16;:1-7

Authors: Miller AM, Pisa P

Numerous immunotherapy trials have been carried out in prostate cancer (PC) patients, with induction of antigen-specific T cells in some cases. Despite this capability, limited success is seen in terms of tumor regression or survival. In this review, we discuss the evidence for tumor escape strategies that may contribute to vaccine failure in the setting of PC. These include defects in antigen presentation, production of immunosuppressive substances, induction of T cell death, T cell receptor dysfunction, and the presence of tolerogenic dendritic cells and regulatory T cells inside prostate tumors. It is clear that novel strategies aimed at preventing tumor escape, such as small molecular weight inhibitors of immunosuppressive molecules, adoptive transfer of TCR transgenic T cells, removal of Tregs, combined with anti-androgen therapy and prostate-specific vaccines, need to be examined further in PC patients.

PMID: 16362411 [PubMed - as supplied by publisher]

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Targeted elimination of prostate cancer by genetically directed human T lymphocytes.

Cancer Res. 2005 Oct 1;65(19):9080-8

Authors: Gade TP, Hassen W, Santos E, Gunset G, Saudemont A, Gong MC, Brentjens R, Zhong XS, Stephan M, Stefanski J, Lyddane C, Osborne JR, Buchanan IM, Hall SJ, Heston WD, Rivi re I, Larson SM, Koutcher JA, Sadelain M

The genetic transfer of antigen receptors is a powerful approach to rapidly generate tumor-specific T lymphocytes. Unlike the physiologic T-cell receptor, chimeric antigen receptors (CARs) encompass immunoglobulin variable regions or receptor ligands as their antigen recognition moiety, thus permitting T cells to recognize tumor antigens in the absence of human leukocyte antigen expression. CARs encompassing the CD3zeta chain as their activating domain induce T-cell proliferation in vitro, but limited survival. The requirements for genetically targeted T cells to function in vivo are less well understood. We have, therefore, established animal models to assess the therapeutic efficacy of human peripheral blood T lymphocytes targeted to prostate-specific membrane antigen (PSMA), an antigen expressed in prostate cancer cells and the neovasculature of various solid tumors. In vivo specificity and antitumor activity were assessed in mice bearing established prostate adenocarcinomas, using serum prostate-secreted antigen, magnetic resonance, computed tomography, and bioluminescence imaging to investigate the response to therapy. In three tumor models, orthotopic, s.c., and pulmonary, we show that PSMA-targeted T cells effectively eliminate prostate cancer. Tumor eradication was directly proportional to the in vivo effector-to-tumor cell ratio. Serial imaging further reveals that the T cells must survive for at least 1 week to induce durable remissions. The eradication of xenogeneic tumors in a murine environment shows that the adoptively transferred T cells do not absolutely require in vivo costimulation to function. These results thus provide a strong rationale for undertaking phase I clinical studies to assess PSMA-targeted T cells in patients with metastatic prostate cancer.

PMID: 16204083 [PubMed - indexed for MEDLINE]

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Targeted elimination of prostate cancer by genetically directed human T lymphocytes.

Cancer Res. 2005 Oct 1;65(19):9080-8

Authors: Gade TP, Hassen W, Santos E, Gunset G, Saudemont A, Gong MC, Brentjens R, Zhong XS, Stephan M, Stefanski J, Lyddane C, Osborne JR, Buchanan IM, Hall SJ, Heston WD, Rivi re I, Larson SM, Koutcher JA, Sadelain M

The genetic transfer of antigen receptors is a powerful approach to rapidly generate tumor-specific T lymphocytes. Unlike the physiologic T-cell receptor, chimeric antigen receptors (CARs) encompass immunoglobulin variable regions or receptor ligands as their antigen recognition moiety, thus permitting T cells to recognize tumor antigens in the absence of human leukocyte antigen expression. CARs encompassing the CD3zeta chain as their activating domain induce T-cell proliferation in vitro, but limited survival. The requirements for genetically targeted T cells to function in vivo are less well understood. We have, therefore, established animal models to assess the therapeutic efficacy of human peripheral blood T lymphocytes targeted to prostate-specific membrane antigen (PSMA), an antigen expressed in prostate cancer cells and the neovasculature of various solid tumors. In vivo specificity and antitumor activity were assessed in mice bearing established prostate adenocarcinomas, using serum prostate-secreted antigen, magnetic resonance, computed tomography, and bioluminescence imaging to investigate the response to therapy. In three tumor models, orthotopic, s.c., and pulmonary, we show that PSMA-targeted T cells effectively eliminate prostate cancer. Tumor eradication was directly proportional to the in vivo effector-to-tumor cell ratio. Serial imaging further reveals that the T cells must survive for at least 1 week to induce durable remissions. The eradication of xenogeneic tumors in a murine environment shows that the adoptively transferred T cells do not absolutely require in vivo costimulation to function. These results thus provide a strong rationale for undertaking phase I clinical studies to assess PSMA-targeted T cells in patients with metastatic prostate cancer.

PMID: 16204083 [PubMed - indexed for MEDLINE]

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Identification of a novel prostate tumor target, mindin/RG-1, for antibody-based radiotherapy of prostate cancer.

Cancer Res. 2005 Sep 15;65(18):8397-405

Authors: Parry R, Schneider D, Hudson D, Parkes D, Xuan JA, Newton A, Toy P, Lin R, Harkins R, Alicke B, Biroc S, Kretschmer PJ, Halks-Miller M, Klocker H, Zhu Y, Larsen B, Cobb RR, Bringmann P, Roth G, Lewis JS, Dinter H, Parry G

Gene expression analysis showed that a human mindin homologue, mindin/RG-1, is expressed selectively in prostate tissues and that its expression level is elevated in some prostate tumors. Mindin/RG-1 protein expression is maintained in >80% of prostate cancers metastatic to bone or lymph nodes as well as in locally recurrent tumors in androgen-unresponsive patients. In contrast, mindin/RG-1 expression in other normal tissues is significantly lower than that seen in the prostate. A fully human antibody, 19G9, was generated against mindin/RG-1 protein and was shown to accumulate at high abundance in LNCaP tumor xenografts. Conjugates of this antibody with the chelator CHX-A''-DTPA were generated and radiolabeled with either 111In, 90Y, or 86Y. Small animal positron emission tomography imaging with the 86Y-radiolabeled conjugate showed very specific accumulation of the antibody in LNCaP tumor xenografts with clear tumor delineation apparent at 4 hours. The therapeutic efficacy of [90Y]-CHX-A''-DTPA-19G9 was evaluated in mice bearing LNCaP xenografts. A dose-finding study identified a nontoxic therapeutic dose to be approximately 75 microCi. Significant antitumor effects were seen with a single administration of radiolabeled antibody to animals bearing 200 to 400 mm3 tumors. Inhibition of tumor growth was observed in all treated animals over a 49-day period. At 49 days posttreatment, slow tumor growth recurred but this could be prevented for an additional 40-day period by a second administration of a 75 microCi dose at day 49. We conclude that [90Y]-CHX-A''-DTPA-19G9 is a novel antibody conjugate that has considerable promise for therapy of metastatic prostate cancer in androgen-unresponsive patients.

PMID: 16166318 [PubMed - indexed for MEDLINE]

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Prediction of myelotoxicity based on bone marrow radiation-absorbed dose: radioimmunotherapy studies using 90Y- and 177Lu-labeled J591 antibodies specific for prostate-specific membrane antigen.

J Nucl Med. 2005 May;46(5):850-8

Authors: Vallabhajosula S, Goldsmith SJ, Hamacher KA, Kostakoglu L, Konishi S, Milowski MI, Nanus DM, Bander NH

In radioimmunotherapy, myelotoxicity due to bone marrow radiation-absorbed dose is the predominant factor and frequently is the dose-limiting factor that determines the maximum tolerated dose (MTD). With (90)Y- and (131)I-labeled monoclonal antibodies, it has been reported that myelotoxicity cannot be predicted on the basis of the amount of radioactive dose administered or the bone marrow radiation-absorbed dose (BMrad), estimated using blood radioactivity concentration. As part of a phase I dose-escalation study in patients with prostate cancer with (90)Y-DOTA-J591 (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) ((90)Y-J591) and (177)Lu-DOTA-J591 ((177)Lu-J591), we evaluated the potential value of several factors in predicting myelotoxicity. METHODS: Seven groups of patients (n = 28) received 370-2,775 MBq/m(2) (10-75 mCi/m(2)) of (177)Lu-J591 and 5 groups of patients (n = 27) received 185-740 MBq (5-20 mCi/m(2)) of (90)Y-J591. Pharmacokinetics and imaging studies were performed for 1-2 wk after (177)Lu treatment, whereas patients receiving (90)Y had these studies performed with (111)In-DOTA-J591 ((111)In-J591) as a surrogate. The BMrad was estimated based on blood radioactivity concentration. Myelotoxicity consisting of thrombocytopenia or neutropenia was graded 1-4 based on criteria of the National Cancer Institute. RESULTS: Blood pharmacokinetics are similar for both tracers. The radiation dose (mGy/MBq) to the bone marrow was 3 times higher with (90)Y (0.91 +/- 0.43) compared with that with (177)Lu (0.32 +/- 0.10). The MTD was 647.5 MBq/m(2) with (90)Y-J591 and 2,590 MBq/m(2) with (177)Lu-J591. The percentage of patients with myelotoxicity (grade 3-4) increased with increasing doses of (90)Y (r = 0.91) or (177)Lu (r = 0.92). There was a better correlation between the radioactive dose administered and the BMrad with (177)Lu (r = 0.91) compared with that with (90)Y (r = 0.75). In addition, with (177)Lu, the fractional decrease in platelets (FDP) correlates well with both the radioactive dose administered (r = 0.88) and the BMrad (r = 0.86). In contrast, with (90)Y, there was poor correlation between the FDP and the radioactive dose administered (r = 0.20) or the BMrad (r = 0.26). Similar results were also observed with white blood cell toxicity. CONCLUSION: In patients with prostate cancer, myelotoxicity after treatment with (177)Lu-J591 can be predicted on the basis of the amount of radioactive dose administered or the BMrad. The lack of correlation between myelotoxicity and (90)Y-J591 BMrad may be due to several factors. (90)Y-J591 may be less stable in vivo and, as a result, higher amounts of free (90)Y may be localized in the bone. In addition, the cross-fire effect of high-energy beta(-)-particles within the bone and the marrow may deliver radiation dose nonuniformly within the marrow.

PMID: 15872360 [PubMed - indexed for MEDLINE]

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Ex vivo expanded human Vgamma9Vdelta2+ gammadelta-T cells mediate innate antitumor activity against human prostate cancer cells in vitro.

J Urol. 2005 May;173(5):1552-6

Authors: Liu Z, Guo BL, Gehrs BC, Nan L, Lopez RD

PURPOSE: We have previously identified a CD2 mediated, interleukin-12 dependent signaling pathway that inhibits activation induced cell death in mitogen stimulated human gammadelta-T cells, permitting the large-scale expansion of these cells. Herein we report the innate antitumor activity of expanded human Vgamma9Vdelta2+ gammadelta-T cells against human prostate cancer cells. MATERIALS AND METHODS: Apoptosis resistant human gammadelta-T cells were expanded in vitro from cultured human peripheral blood mononuclear cells and then enriched to high purity by immunomagnetic separation. In vitro cytotoxicity of expanded gammadelta-T cells was measured against human prostate cancer cell lines using standard cytotoxicity assays. RESULTS: gammadelta-T cells derived from various donors consistently showed lytic activity against the prostate cancer cell lines DU-145 and PC-3 but not LNCaP. mAbs against Vgamma9 or Vdelta2 T-cell receptor chains as well as mAb against intercellular adhesion molecule-1 (ICAM-1) or CD18, the beta subunit of ICAM-1 counter receptors, blocked gammadelta-T cell mediated killing of prostate cancer cells. gammadelta-T cells lysed prostate cancer cell lines largely through the perforin/granzyme pathway. CONCLUSIONS: Ex vivo, expanded human Vgamma9Vdelta2+ gammadelta-T cells are able innately to recognize and kill certain human prostate tumor cell lines in vitro. The recognition and killing of prostate cancer cells occurs in a gammadelta-T-cell receptor dependent manner and it also appears to involve interactions between ICAM-1 and CD18. Because apoptosis resistant human Vgamma9Vdelta2+ gammadelta-T cells can readily be expanded to large numbers (clinical scale), these findings must be considered in the context of developing adoptive immunotherapy strategies to exploit gammadelta-T cell innate immune responses to prostate cancer.

PMID: 15821484 [PubMed - indexed for MEDLINE]

Posted by at 12:15 PM | Permalink

Related Articles

Tissue-specificity of prostate specific antigens: Comparative analysis of transcript levels in prostate and non-prostatic tissues.

Cancer Lett. 2005 Jul 18;

Authors: Cunha AC, Weigle B, Kiessling A, Bachmann M, Rieber EP

Activation of immune defense mechanisms against tumor antigens appears to be a promising therapeutic option for advanced prostate cancer (PCa). Specific immunotherapy critically depends on target antigens that are selectively expressed in the tumorous and optional in the normal prostate tissue in sufficient amounts. Although several prostate antigens have been described and some have already been used in clinical trials, a detailed comparative evaluation of their tissue-specificity and expression levels is still lacking. We determined the transcript levels of eight prostate targets (PSA, PAP, PSCA, PSGR, Prostein, PSMA, AIbZIP, trp-p8) in 16 different tissues by quantitative PCR and calculated a tissue-specificity index (TSI) for each molecule. Besides a preferential expression in prostate for all targets, striking differences in the expression levels and TSI were revealed which may be important for the selection of appropriate antigens for immunotherapy of PCa.

PMID: 16046056 [PubMed - as supplied by publisher]

Posted by at 8:25 PM | Permalink

Highlights from the 41st Annual Meeting of the American Society of Clinical Oncology, May 2005, and the 2005 American Society of Clinical Oncology Prostate Cancer Symposium, February 2005, Orlando, Florida.

Clin Prostate Cancer. 2005 Jun;4(1):7-14

Authors: Reddy GK, Tyagi P

PMID: 15992456 [PubMed - indexed for MEDLINE]

Posted by at 1:57 PM | Permalink

Gene therapy and immunotherapy of prostate cancer: adenoviral-based strategies.

Acta Oncol. 2005;44(6):610-27

Authors: Essand M

PMID: 16165921 [PubMed - in process]

Posted by at 10:24 PM | Permalink

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Recognition of prostate and breast tumor cells by helper T lymphocytes specific for a prostate and breast tumor-associated antigen, TARP.

Clin Cancer Res. 2005 May 15;11(10):3869-78

Authors: Kobayashi H, Nagato T, Oikawa K, Sato K, Kimura S, Aoki N, Omiya R, Tateno M, Celis E

PURPOSE: T cell-based immunotherapy via the in vitro or in vivo expansion of prostate tumor-associated antigen (TAA)-specific T lymphocytes is one of the most promising therapeutic approaches to treat prostate cancer. T-cell alternate reading frame protein (TARP) is a mitochondrial protein that is specifically expressed in prostate epithelial cells. We have done experiments aimed at identifying helper T lymphocyte (HTL) epitopes for TARP for the design of T cell-based immunotherapy for prostate cancer. EXPERIMENTAL DESIGN: Dendritic cells from normal donors were pulsed with synthetic peptides derived from TARP, which were predicted to serve as HTL epitopes. These dendritic cells were used to stimulate CD4(+) T cells in vitro to trigger HTL responses against TARP. T-cell responses to these peptides were also studied with lymphocytes from prostate cancer patients. RESULTS: The two peptides, TARP(1-14) and TARP(14-27), were shown to elicit effective in vitro HTL responses using lymphocytes from both normal volunteers and prostate cancer patients. Peptide TARP(1-14)-reactive HTLs were found restricted by HLA-DR53 and could recognize naturally processed protein antigen derived from tumor cells, which was presented by autologous dendritic cells. Most significantly, stimulation with peptide TARP(14-27) generated four HTL lines restricted by HLA-DR1, HLA-DR9, HLA-DR13, and HLA-DR15, some of which capable of recognizing naturally processed antigens presented by dendritic cell or directly by TARP-positive tumor cells. CONCLUSIONS: Our results show that TARP constitutes a TAA that can be recognized by tumor-reactive HTL. The newly described TARP epitopes could be used to optimize and improve T-cell epitope-based immunotherapy against prostate and other tumors expressing TARP.

PMID: 15897588 [PubMed - indexed for MEDLINE]

Posted by at 8:23 PM | Permalink

[Expression of prostate stem cell antigen (PSCA) and selection of its specific binding peptide]

Sheng Wu Gong Cheng Xue Bao. 2004 Sep;20(5):694-8

Authors: Hou LH, Du Y, Zhang XP, An XP, Chen W

Prostate stem cell antigen (PSCA), a homologue of the Ly-6/Thy-1 family of cell surface antigen, is expressed by a majority of human prostate cancers and is a promising target for prostate cancer immunotherapy. To obtain the specific peptide binding with PSCA for targeted immunotherapy, PSCA gene was obtained by RT-PCR from human prostate cancer cell line DU145 and the transcated PSCA (tPSCA) gene was cloned into vector pQE30 for soluble expression in E. coli. The identity of recombinant tPSCA was confirmed through ELISA and western blot by use of anti-PSCA monoclonal antibody. Then the 12-peptide phage display library was screened with the purified tPSCA protein for its specific binding peptide through 3 rounds panning. For identifying the peptide's specificity, the peptide was coupled with EGFP (enhanced green fluorecent protein) by recombinant DNA technology and the recombinant coupled protein was termed 11-EGFP. The binding specificity with tPSCA of 11-EGFP was further confirmed by ELISA and competitive inhibition experiment. Flow cytometry demonstrated its binding specificity with cell line DU145. In conclusion, a 12-amino-acid peptide which could bind with PSCA specifically was found and it may be a potential tool for targeted immunotherapy of prostate carcinoma.

PMID: 15973992 [PubMed - in process]

Posted by at 10:10 PM | Permalink

Advanced prostate cancer: the future.

Can J Urol. 2005 Jun;12 Suppl 2:42-7

Authors: Armstrong AJ, Carducci MA

The demonstration of a survival benefit with docetaxel for the treatment of metastatic hormone refractory prostate cancer (HRPC) is an important step forward in advancing treatment options for advanced prostate cancer. While docetaxel-based therapy has demonstrated improvement in symptomatic and quality-of-life endpoints, certainly there is a pressing need for improvement in outcomes. A number of novel agents are in basic and clinical development for advanced prostate cancer, some of which are specific to mechanisms that may be important in the development and spread of prostate cancer. Novel approaches including novel cytotoxics, immunotherapy, PSMA targeted monoclonal antibodies are among the broad categories that will be discussed in this brief review.

PMID: 16018833 [PubMed - indexed for MEDLINE]

Posted by at 1:10 PM | Permalink

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Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer.

Clin Cancer Res. 2005 Oct 15;11(20):7454-61

Authors: Morris MJ, Divgi CR, Pandit-Taskar N, Batraki M, Warren N, Nacca A, Smith-Jones P, Schwartz L, Kelly WK, Slovin S, Solit D, Halpern J, Delacruz A, Curley T, Finn R, O'donoghue JA, Livingston P, Larson S, Scher HI

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored. PATIENTS AND METHODS: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed. RESULTS: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline. CONCLUSIONS: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.

PMID: 16243819 [PubMed - in process]

Posted by at 1:41 PM | Permalink

Novel therapeutic approaches to advanced prostate cancer.

Clin Adv Hematol Oncol. 2005 Apr;3(4):271-82

Authors: Armstrong AJ, Carducci MA

Considerable progress in the treatment of advanced prostate cancer was made in 2004 with the approval by the US Food and Drug Administration of docetaxel for the treatment of metastatic hormone-refractory prostate cancer. The survival benefit with docetaxel and prednisone, however, has been modest, on the order of 2-3 months compared with mitoxantrone and prednisone. While docetaxel-based therapy has demonstrated improvement in symptomatic and quality-of-life endpoints, certainly there is a pressing need for improvement in outcomes. A number of novel agents are in basic and clinical development for advanced prostate cancer, some of which are specific to mechanisms that may be important in the development and spread of prostate cancer. Novel approaches including immunotherapy, antiangiogenic compounds, and cell growth and survival pathway inhibitors, as well as targeted cytotoxic compounds, are among the broad categories that will be discussed in this review. Clinical advances in meaningful endpoints such as survival and quality of life are eagerly awaited in large-scale trials of active and rationally designed agents.

PMID: 16167000 [PubMed - in process]

Posted by at 7:53 PM | Permalink

Related Articles

Tissue-specificity of prostate specific antigens: Comparative analysis of transcript levels in prostate and non-prostatic tissues.

Cancer Lett. 2005 Jul 18;

Authors: Cunha AC, Weigle B, Kiessling A, Bachmann M, Rieber EP

Activation of immune defense mechanisms against tumor antigens appears to be a promising therapeutic option for advanced prostate cancer (PCa). Specific immunotherapy critically depends on target antigens that are selectively expressed in the tumorous and optional in the normal prostate tissue in sufficient amounts. Although several prostate antigens have been described and some have already been used in clinical trials, a detailed comparative evaluation of their tissue-specificity and expression levels is still lacking. We determined the transcript levels of eight prostate targets (PSA, PAP, PSCA, PSGR, Prostein, PSMA, AIbZIP, trp-p8) in 16 different tissues by quantitative PCR and calculated a tissue-specificity index (TSI) for each molecule. Besides a preferential expression in prostate for all targets, striking differences in the expression levels and TSI were revealed which may be important for the selection of appropriate antigens for immunotherapy of PCa.

PMID: 16046056 [PubMed - as supplied by publisher]

Posted by at 4:09 PM | Permalink