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Ira Pastan - One of the best experts on this subject based on the ideXlab platform.

  • anti Mesothelin recombinant immunotoxin therapy for colorectal cancer
    Clinical Colorectal Cancer, 2019
    Co-Authors: Adam Cerise, Xiu Fen Liu, Tapan K Bera, Junxia Wei, Ira Pastan
    Abstract:

    Abstract Background Mesothelin (MSLN) is a cell surface glycoprotein expressed at high level on many malignancies, including pancreatic adenocarcinoma, serous ovarian cancer, and epithelioid mesothelioma. MSLN-targeted recombinant immunotoxins (RITs) consist of an anti-MSLN Fv fused to the catalytic domain of Pseudomonas exotoxin A. Recent data has also shown that MSLN is expressed at clinically relevant levels on the surface of colorectal cancer. In this study, colorectal cell lines were tested for Mesothelin expression and susceptibility to MSLN-targeted RIT. Materials and Methods Colorectal cancer (CRC) cell lines were tested for membranous MSLN expression via flow cytometry. Cell lines expressing MSLN were tested by WST-8 cell viability assay for sensitivity to various RITs and chemotherapeutic agents. CRC cell line SW-48 was tested in a mouse model for response to RIT as a single agent or in combination with Actinomycin D and Oxaliplatin. Results CRC cell lines were susceptible to anti-MSLN RITs at IC50 levels comparable to those previously described in pancreatic cancer cell lines. In a nude mouse model, MSLN-targeted RIT treatment of SW48 CRC tumors resulted in a significant decrease in tumor volume. While combination therapy with standard of care chemotherapeutic Oxaliplatin did not improve tumor regressions, combination therapy with Actinomycin D resulted in >90% tumor volume reduction with 50% complete regressions. Conclusions These data support the development of anti-Mesothelin RITs as well as other Mesothelin-targeted therapies for CRC.

  • abstract 58 local intratumoral treatment with anti Mesothelin immunotoxins overcomes resistance to anti ctla 4 therapy
    Cancer Research, 2017
    Co-Authors: Yasmin Leshem, Tapan K Bera, Xiu Fen Liu, Gerhard Niederfellner, Masaki Terabe, Jay A Berzofsky, Birgit Bossenmaier, James P Obrien, Yoram Reiter, Ira Pastan
    Abstract:

    Background: SS1P and RG7787 are immunotoxins composed of anti-Mesothelin antibody fused to a fragment from pseudomonas exotoxin A. We previously observed delayed tumor responses in patients treated with SS1P leading us to hypothesis that immunotoxins can provoke anti-tumor immunity. We hypothesize that intra-tumoral injection of SS1P or RG7787 will produce immunologic death and convert living tumors to a source of antigens and boost the therapeutic effect of immune check point blockade. Method: A BALB/c breast cancer cell line was transfected with human Mesothelin (66C14-M) and grown in BALB/c mice transgenic for human Mesothelin. SS1P or RG7787 was injected directly into established tumors (80-100 mm3) and anti-CTLA-4 administered IP. Results: We observed total tumor regressions in 23 out of 38 mice (60%) treated with anti-CTLA-4 and either RG7787 or SS1P. No cure was achieved when the drugs were given as a monotherapy supporting the case for synergic anti-tumor activity. Pathologic evaluation of regressing tumors showed a massive inflammation of admixed eosinophils and mononuclear cells located in a collar surrounding the tumors. Tumor regression was associated with increased number of CD8+ cells and was blocked when CD8+ cells were depleted by an antibody. In addition, cured mice were resistant to re-implantation of 66C14 cells not expressing Mesothelin indicating that a long-term anti-tumor immunity was formed. To determine if pathogen associated molecular patterns contributed to the response, we combined anti-CTLA-4 with an inactive RG7787 and observed a major reduction in anti-tumor activity (P Conclusions: We suggest that injecting immunotoxins into tumors is a useful approach to boost the activity of anti-CTLA-4. Based on the synergistic anti-tumor effect demonstrated in this study we believe that there is a strong rational to explore such combination therapies in patients. Citation Format: Yasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Jay A. Berzofsky, Birgit Bossenmaier, Gerhard Niederfellner, James O9Brien, Yoram Reiter, Ira Pastan. Local intratumoral treatment with anti-Mesothelin Immunotoxins overcomes resistance to anti-CTLA-4 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 58. doi:10.1158/1538-7445.AM2017-58

  • efficacy of anti Mesothelin immunotoxin rg7787 plus nab paclitaxel against mesothelioma patient derived xenografts and Mesothelin as a biomarker of tumor response
    Clinical Cancer Research, 2017
    Co-Authors: Jingli Zhang, Ira Pastan, Christine Alewine, Markku Miettinen, Swati Khanna, Qun Jiang, Raffit Hassan
    Abstract:

    Purpose: The purpose of this study was to evaluate the antitumor efficacy of the reduced immunogenicity anti-Mesothelin immunotoxin RG7787 plus nab-paclitaxel against primary mesothelioma cell lines and tumor xenografts and the utility of Mesothelin as a biomarker of tumor response.Experimental Design: Early-passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21, and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-paclitaxel alone or in combination. In addition, the antitumor activity of RG7787 plus nab-paclitaxel was evaluated using NCI-Meso16, NCI-Meso21, and NCI-Meso29 tumor xenografts in immunodeficient mice. Serum Mesothelin was measured at different time points to determine whether its levels correlated with tumor response.Results: All four primary mesothelioma cell lines highly expressed Mesothelin with 41 × 103 to 346 × 103 Mesothelin sites per cell and were sensitive to RG7787, with IC50 ranging from 0.3 to 10 ng/mL. Except for NCI-Meso19, these cells were also sensitive to nab-paclitaxel, with IC50 of 10 to 25 ng/mL. In vitro, RG7787 plus nab-paclitaxel led to decreased cell viability compared with either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar antitumor efficacy was observed against NCI-Meso21 and NCI-Meso29 tumor xenografts. In all three tumor xenograft models, changes in human serum Mesothelin correlated with response to therapy and were undetectable in mice with complete tumor regression with RG7787 and nab-paclitaxel.Conclusions: RG7787 plus nab-paclitaxel is very active against primary human mesothelioma cells in vitro as well as in vivo, with serum Mesothelin levels correlating with tumor response. These results indicate that this combination could be useful for treating patients with mesothelioma. Clin Cancer Res; 23(6); 1564-74. ©2016 AACR.

  • expression of Mesothelin in thymic carcinoma and its potential therapeutic significance
    Lung Cancer, 2016
    Co-Authors: Anish Thomas, Ira Pastan, Yuanbin Chen, Seth M Steinberg, Giuseppe Giaccone, Arlene Berman, David S Schrump, David Venzon, David J Liewehr, Markku Miettinen
    Abstract:

    Abstract Objectives Advanced thymic epithelial tumors (TETs) lack adequate treatment options in part due to absence of well characterized tumor-specific antigens. Mesothelin, a cell surface antigen, has been used successfully as a target for tumor-directed therapy. We sought to determine tumor expression and serum levels of Mesothelin in patients with TETs. Patients and methods Tissue samples were obtained from 71 patients with histologically confirmed, unresectable advanced TETs and evaluated for Mesothelin expression by immunohistochemistry. The evaluation was blinded for clinical data and outcome. Mesothelin expression and its association with clinico-pathological parameters and survival were assessed. Results Thymic carcinoma, thymoma, and thymic neuroendocrine tumors (NETs) accounted for 34 (48%), 29 (41%), and 8 (11%) cases respectively. Mesothelin expression was seen in a significantly larger proportion of thymic carcinoma (27/34, 79%) than thymoma (3/29, 10%) (P 50% of tumor cells) had significantly improved overall survival (median not reached, n=19) compared to patients with no or low Mesothelin expression (1.60 years; 95% CI: 1.24–4.94 years; n=15; HR=4.46, 95% CI: 1.55–12.80; p=0.0026). Conclusion Mesothelin expression is frequently observed in advanced thymic carcinomas, infrequently in thymomas and is absent in thymic NETs. Due to strong, membranous expression Mesothelin is a potential therapeutic target in thymic carcinoma.

  • actinomycin d enhances killing of cancer cells by immunotoxin rg7787 through activation of the extrinsic pathway of apoptosis
    Proceedings of the National Academy of Sciences of the United States of America, 2016
    Co-Authors: Xiu Fen Liu, Laiman Xiang, Qi Zhou, Jeanphilippe Carralot, Marco Prunotto, Gerhard Niederfellner, Ira Pastan
    Abstract:

    RG7787 is a Mesothelin-targeted immunotoxin designed to have low-immunogenicity, high-cytotoxic activity and fewer side effects. RG7787 kills many types of Mesothelin-expressing cancer cells lines and causes tumor regressions in mice. Safety and immunogenicity of RG7787 is now being assessed in a phase I trial. To enhance the antitumor activity of RG7787, we screened for clinically used drugs that can synergize with RG7787. Actinomycin D is a potent transcription inhibitor that is used for treating several cancers. We report here that actinomycin D and RG7787 act synergistically to kill many Mesothelin-positive cancer cell lines and produce major regressions of pancreatic and stomach cancer xenografts. Analyses of RNA expression show that RG7787 or actinomycin D alone and together increase levels of TNF/TNFR family members and NF-κB–regulated genes. Western blots revealed the combination changed apoptotic protein levels and enhanced cleavage of Caspases and PARP.

Raffit Hassan - One of the best experts on this subject based on the ideXlab platform.

  • abstract ct105 preliminary safety and efficacy of gavocabtagene autoleucel gavo cel tc 210 a t cell receptor fusion construct truc in patients with treatment refractory Mesothelin overexpressing solid tumors
    Clinical Trials, 2021
    Co-Authors: David S Hong, Janos L Tanyi, Melissa Lynne Johnson, Lauren Macmullen, Robert Tighe, Lizzy Jalbert, Viera P Muzithras, Kevin Zikaras, Alfonso Quintas Cardama, Raffit Hassan
    Abstract:

    Background: Mesothelin overexpression is present in over 80,000 patients/year with either malignant mesothelioma (MPM), ovarian cancer, cholangiocarcinoma, or non-small cell lung cancer (NSCLC) in the U.S. alone. We are testing a novel genetically engineered anti-Mesothelin TRuC™ T cell therapy called gavo-cel (TC-210) in a Phase 1 study in treatment refractory patients with any of the four aforementioned cancers (NCT03907852). Methods: Gavo-cel was engineered by transducing T cells with a lentiviral vector encoding for an anti-Mesothelin llama-derived single domain antibody fused to the CD3epsilon subunit using a flexible glycine serine sequence. Upon translation, gavo-cel TRuCs integrate and reprogram intact TCR complexes to recognize tumor surface Mesothelin in an HLA-independent manner. Eligibility criteria required demonstration of Mesothelin overexpression on tumors (≥50% of tumor cells expressing 2+ or 3+ staining by IHC) at a central laboratory. Gavo-cel dose escalation proceeded following a modified 3+3 schema. TC-210 expansion and serum cytokine levels were serially measured. Results: Seven patients (6 MPM, 1 ovarian) received a single gavo-cel intravenous infusion at the initial dose of 5x107/m2 either alone (dose level [DL] 0, n=1) or following lymphodepletion (LD) (DL1, n=6) with fludarabine (30mg/m2/day x4) and cyclophosphamide (600mg/m2/day x3). The median age was 69 years (range, 36-84) and the median number of prior therapies was 5 (range, 2-9). Four patients had received ≥4 lines of therapy, including immune checkpoint inhibitors (n=5), the anti-Mesothelin ADC anetumab ravtansine (n=1), and anti-Mesothelin mRNA CAR-T (n=1). Four patients required bridging therapy. No on-target/off-tumor toxicities or neurotoxicity events of any grade were observed. Grade (gr) ≥3 treatment emergent AEs occurred in 2 (29%) patients with MPM treated at DL1: 1 with gr3 CRS, and 1 with gr3 CRS, gr3 pneumonitis and gr5 fungal sepsis (unrelated to gavo-cel). CRS and pneumonitis events resolved with tocilizumab and corticosteroids. Grade 3 pneumonitis was considered a DLT, resulting in DL1 cohort expansion to 6 patients. At data cut-off date (November 8, 2020), 6 patients have been followed for >3 months, including 4 followed through month 6. The disease control rate was 100%. All patients experienced target lesion regression by CT: median 61% (range, 5-75%). Three (43%) patients (2 with mesothelioma and 1 with ovarian cancer) had a partial response by RECIST v1.1 criteria, including 1 achieving a complete metabolic response. After a median follow-up of 6.5 months, the median OS at 6 months was (86%). The addition of LD increased TC-210 peak expansion and persistence, with cells being detected up to 30 days post infusion in peripheral blood. Conclusion: Intravenous systemic administration of gavo-cel was generally safe and resulted in three of seven patients having objective partial response. Dose escalation is ongoing at 1x108/m2. Updated clinical and translational data will be presented. Citation Format: David S. Hong, Melissa Johnson, Janos L. Tanyi, Lauren MacMullen, Robert Tighe, Lizzy Jalbert, Viera P. Muzithras, Kevin Zikaras, Alfonso Quintas Cardama, Raffit Hassan. Preliminary safety and efficacy of gavocabtagene autoleucel (gavo-cel, TC-210), a T cell receptor fusion construct (TRuC™), in patients with treatment refractory Mesothelin overexpressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT105.

  • efficacy of anti Mesothelin immunotoxin rg7787 plus nab paclitaxel against mesothelioma patient derived xenografts and Mesothelin as a biomarker of tumor response
    Clinical Cancer Research, 2017
    Co-Authors: Jingli Zhang, Ira Pastan, Christine Alewine, Markku Miettinen, Swati Khanna, Qun Jiang, Raffit Hassan
    Abstract:

    Purpose: The purpose of this study was to evaluate the antitumor efficacy of the reduced immunogenicity anti-Mesothelin immunotoxin RG7787 plus nab-paclitaxel against primary mesothelioma cell lines and tumor xenografts and the utility of Mesothelin as a biomarker of tumor response.Experimental Design: Early-passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21, and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-paclitaxel alone or in combination. In addition, the antitumor activity of RG7787 plus nab-paclitaxel was evaluated using NCI-Meso16, NCI-Meso21, and NCI-Meso29 tumor xenografts in immunodeficient mice. Serum Mesothelin was measured at different time points to determine whether its levels correlated with tumor response.Results: All four primary mesothelioma cell lines highly expressed Mesothelin with 41 × 103 to 346 × 103 Mesothelin sites per cell and were sensitive to RG7787, with IC50 ranging from 0.3 to 10 ng/mL. Except for NCI-Meso19, these cells were also sensitive to nab-paclitaxel, with IC50 of 10 to 25 ng/mL. In vitro, RG7787 plus nab-paclitaxel led to decreased cell viability compared with either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar antitumor efficacy was observed against NCI-Meso21 and NCI-Meso29 tumor xenografts. In all three tumor xenograft models, changes in human serum Mesothelin correlated with response to therapy and were undetectable in mice with complete tumor regression with RG7787 and nab-paclitaxel.Conclusions: RG7787 plus nab-paclitaxel is very active against primary human mesothelioma cells in vitro as well as in vivo, with serum Mesothelin levels correlating with tumor response. These results indicate that this combination could be useful for treating patients with mesothelioma. Clin Cancer Res; 23(6); 1564-74. ©2016 AACR.

  • recombinant immunotoxin with t cell epitope mutations that greatly reduce immunogenicity for treatment of Mesothelin expressing tumors
    Molecular Cancer Therapeutics, 2015
    Co-Authors: Ronit Mazor, Raffit Hassan, Jingli Zhang, Richard Beers, Laiman Xiang, Selamawit Addissie, Prince Awuah, Ira Pastan
    Abstract:

    SS1P is a recombinant immunotoxin (RIT) that targets Mesothelin. It consists of an antiMesothelin Fv fused to a portion of Pseudomonas exotoxin A. In clinical studies, it has produced dramatic responses in patients with advanced mesothelioma, when combined with immunosuppressive therapy so that several treatment cycles could be given. Otherwise its activity is limited by its immunogenicity. In this work, we describe the development and characterization of LMB-T20, a highly potent RIT targeted at Mesothelin-expressing cancers with low immunogenicity due to removal of its eight T-cell epitopes. LMB-T20 was more active than SS1P when tested on four different Mesothelin-expressing cell lines as well as on cells obtained from patients with mesothelioma. It also has potent antitumor activity in mice, and has reduced immunogenicity as measured by cytokine secretion assays. In conclusion, LMB-T20 is a favorable candidate for evaluation in clinical trials due to its reduced immunogenicity and excellent activity.

  • New High Affinity Monoclonal Antibodies Recognize Non-Overlapping Epitopes On Mesothelin For Monitoring And Treating Mesothelioma
    Scientific Reports, 2015
    Co-Authors: Yi-fan Zhang, Raffit Hassan, Wei Gao, Yen Phung, Seiji Kawa, Ira Pastan
    Abstract:

    Mesothelin is an emerging cell surface target in mesothelioma and other solid tumors. Most antibody drug candidates recognize highly immunogenic Region I (296–390) on Mesothelin. Here, we report a group of high-affinity non-Region I rabbit monoclonal antibodies. These antibodies do not compete for Mesothelin binding with the immunotoxin SS1P that binds Region I of Mesothelin. One pair of antibodies (YP218 and YP223) is suitable to detect soluble Mesothelin in a sandwich ELISA with high sensitivity. The new assay can also be used to measure serum Mesothelin concentration in mesothelioma patients, indicating its potential use for monitoring patients treated with current antibody therapies targeting Region I. The antibodies are highly specific and sensitive in immunostaining of mesothelioma. To explore their use in tumor therapy, we have generated the immunotoxins based on the Fv of these antibodies. One immunotoxin (YP218 Fv-PE38) exhibits potent anti-tumor cytotoxicity towards primary mesothelioma cell lines in vitro and an NCI-H226 xenograft tumor in mice. Furthermore, we have engineered a humanized YP218 Fv that retains full binding affinity for Mesothelin-expressing cancer cells. In conclusion, with their unique binding properties, these antibodies may be promising candidates for monitoring and treating mesothelioma and other Mesothelin-expressing cancers.

  • discovery of Mesothelin and exploiting it as a target for immunotherapy
    Cancer Research, 2014
    Co-Authors: Ira Pastan, Raffit Hassan
    Abstract:

    We have recently reported that an immunotoxin targeting Mesothelin produced durable major tumor regressions in patients with extensive treatment-refractory mesothelioma. These unprecedented tumor responses have prompted us to review how Mesothelin was discovered and the advances that led to these tumor responses. This review is not comprehensive but focuses on major developments over the past 20 years since Mesothelin was first identified in our laboratory. Mesothelin is a cell-surface glycoprotein whose expression in normal human tissues is restricted to mesothelial cells. Because it is highly expressed by many solid tumors, it is an attractive immunotherapy target. Antibody-based therapies currently in clinical trials include an immunotoxin, a chimeric monoclonal antibody, and an antibody drug conjugate. In addition, a Mesothelin tumor vaccine and a Mesothelin- chimeric antigen receptor are being evaluated in the clinic. SS1P, an anti-Mesothelin immunotoxin, was the first Mesothelin-directed therapy to enter the clinic, and its use showed that Mesothelin-targeted therapy was safe in patients. More importantly, our recent work has shown that SS1P in combination with pentostatin and cyclophosphamide can result in durable tumor regression in patients with advanced mesothelioma and opens up the possibility that such an approach can benefit patients with many common cancers.

Tapan K Bera - One of the best experts on this subject based on the ideXlab platform.

  • anti Mesothelin recombinant immunotoxin therapy for colorectal cancer
    Clinical Colorectal Cancer, 2019
    Co-Authors: Adam Cerise, Xiu Fen Liu, Tapan K Bera, Junxia Wei, Ira Pastan
    Abstract:

    Abstract Background Mesothelin (MSLN) is a cell surface glycoprotein expressed at high level on many malignancies, including pancreatic adenocarcinoma, serous ovarian cancer, and epithelioid mesothelioma. MSLN-targeted recombinant immunotoxins (RITs) consist of an anti-MSLN Fv fused to the catalytic domain of Pseudomonas exotoxin A. Recent data has also shown that MSLN is expressed at clinically relevant levels on the surface of colorectal cancer. In this study, colorectal cell lines were tested for Mesothelin expression and susceptibility to MSLN-targeted RIT. Materials and Methods Colorectal cancer (CRC) cell lines were tested for membranous MSLN expression via flow cytometry. Cell lines expressing MSLN were tested by WST-8 cell viability assay for sensitivity to various RITs and chemotherapeutic agents. CRC cell line SW-48 was tested in a mouse model for response to RIT as a single agent or in combination with Actinomycin D and Oxaliplatin. Results CRC cell lines were susceptible to anti-MSLN RITs at IC50 levels comparable to those previously described in pancreatic cancer cell lines. In a nude mouse model, MSLN-targeted RIT treatment of SW48 CRC tumors resulted in a significant decrease in tumor volume. While combination therapy with standard of care chemotherapeutic Oxaliplatin did not improve tumor regressions, combination therapy with Actinomycin D resulted in >90% tumor volume reduction with 50% complete regressions. Conclusions These data support the development of anti-Mesothelin RITs as well as other Mesothelin-targeted therapies for CRC.

  • abstract 58 local intratumoral treatment with anti Mesothelin immunotoxins overcomes resistance to anti ctla 4 therapy
    Cancer Research, 2017
    Co-Authors: Yasmin Leshem, Tapan K Bera, Xiu Fen Liu, Gerhard Niederfellner, Masaki Terabe, Jay A Berzofsky, Birgit Bossenmaier, James P Obrien, Yoram Reiter, Ira Pastan
    Abstract:

    Background: SS1P and RG7787 are immunotoxins composed of anti-Mesothelin antibody fused to a fragment from pseudomonas exotoxin A. We previously observed delayed tumor responses in patients treated with SS1P leading us to hypothesis that immunotoxins can provoke anti-tumor immunity. We hypothesize that intra-tumoral injection of SS1P or RG7787 will produce immunologic death and convert living tumors to a source of antigens and boost the therapeutic effect of immune check point blockade. Method: A BALB/c breast cancer cell line was transfected with human Mesothelin (66C14-M) and grown in BALB/c mice transgenic for human Mesothelin. SS1P or RG7787 was injected directly into established tumors (80-100 mm3) and anti-CTLA-4 administered IP. Results: We observed total tumor regressions in 23 out of 38 mice (60%) treated with anti-CTLA-4 and either RG7787 or SS1P. No cure was achieved when the drugs were given as a monotherapy supporting the case for synergic anti-tumor activity. Pathologic evaluation of regressing tumors showed a massive inflammation of admixed eosinophils and mononuclear cells located in a collar surrounding the tumors. Tumor regression was associated with increased number of CD8+ cells and was blocked when CD8+ cells were depleted by an antibody. In addition, cured mice were resistant to re-implantation of 66C14 cells not expressing Mesothelin indicating that a long-term anti-tumor immunity was formed. To determine if pathogen associated molecular patterns contributed to the response, we combined anti-CTLA-4 with an inactive RG7787 and observed a major reduction in anti-tumor activity (P Conclusions: We suggest that injecting immunotoxins into tumors is a useful approach to boost the activity of anti-CTLA-4. Based on the synergistic anti-tumor effect demonstrated in this study we believe that there is a strong rational to explore such combination therapies in patients. Citation Format: Yasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Jay A. Berzofsky, Birgit Bossenmaier, Gerhard Niederfellner, James O9Brien, Yoram Reiter, Ira Pastan. Local intratumoral treatment with anti-Mesothelin Immunotoxins overcomes resistance to anti-CTLA-4 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 58. doi:10.1158/1538-7445.AM2017-58

  • Mesothelin expression in human lung cancer
    Clinical Cancer Research, 2007
    Co-Authors: Tapan K Bera, Raffit Hassan, Masanori Onda, Mark C Willingham, David J Fitzgerald, Ira Pastan
    Abstract:

    Purpose: To investigate Mesothelin as a new target for immunotherapy in lung cancer. Experimental Design: Mesothelin mRNA and protein expression were assessed by reverse transcription-PCR, immunoblotting, and immunohistochemistry in human lung cancer specimens. Expression was also characterized in human lung cancer cell lines by flow cytometry and immunoblotting. The SS1P immunotoxin specific for Mesothelin was assessed for its cytotoxic activity against lung cancer cells. Results: We found that Mesothelin mRNA was expressed in 83% of lung adenocarcinomas (10 of 12 patients). The Mesothelin precursor protein was detected in 82% of lung adenocarcinoma (9 of 11 patients), and its mature form was detected in 55% (6 of 11 patients). Immunohistochemistry showed strong and diffuse Mesothelin staining in human lung adenocarcinomas and weak or modest staining in squamous cell carcinomas. We detected Mesothelin mRNA in 78% of lung cancer cell lines (7 of 9) of the NCI-60 cell line panel. Mesothelin mRNA and proteins were expressed at a high level in non–small cell lung cancer lines EKVX, NCI-H460, NCI-H322M, and NCI-H522. Flow cytometric analysis showed high surface expression of Mesothelin in NCI-H322M and EKVX cell lines. Immunotoxin SS1P showed high cytotoxic activity on NCI-H322M and EKVX cells with IC 50 values ranging from 2 to 5 ng/mL. Conclusions: Mesothelin is expressed on the surface of most lung adenocarcinoma cells. Immunotoxin SS1P is cytotoxic against Mesothelin-expressing lung cancer cell lines and merits evaluation as a new therapeutic agent in treating non–small cell lung cancer.

  • Mesothelin muc16 binding is a high affinity n glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors
    Molecular Cancer, 2006
    Co-Authors: Jennifer A A Gubbels, Masanori Onda, Tapan K Bera, Jennifer A Belisle, Claudine Rancourt, Martine Migneault, Joseph P Connor, Bangalore K Sathyanarayana, Byungkook Lee, Ira Pastan
    Abstract:

    The mucin MUC16 and the glycosylphosphatidylinositol anchored glycoprotein Mesothelin likely facilitate the peritoneal metastasis of ovarian tumors. The biochemical basis and the kinetics of the binding between these two glycoproteins are not clearly understood. Here we have addressed this deficit and provide further evidence supporting the role of the MUC16-Mesothelin interaction in facilitating cell-cell binding under conditions that mimic the peritoneal environment. In this study we utilize recombinant-Fc tagged human Mesothelin to measure the binding kinetics of this glycoprotein to MUC16 expressed on the ovarian tumor cell line OVCAR-3. OVCAR-3 derived sublines that did not express MUC16 showed no affinity for Mesothelin. In a flow cytometry-based assay Mesothelin binds with very high affinity to the MUC16 on the OVCAR-3 cells with an apparent Kd of 5–10 nM. Maximum interaction occurs within 5 mins of incubation of the recombinant Mesothelin with the OVCAR-3 cells and significant binding is observed even after 10 sec. A five-fold molar excess of soluble MUC16 was unable to completely inhibit the binding of Mesothelin to the OVCAR-3 cells. Oxidation of the MUC16 glycans, removal of its N-linked oligosaccharides, and treatment of the mucin with wheat germ agglutinin and erythroagglutinating phytohemagglutinin abrogates its binding to Mesothelin. These observations suggest that at least a subset of the MUC16-asscociated N-glycans is required for binding to Mesothelin. We also demonstrate that MUC16 positive ovarian tumor cells exhibit increased adherence to A431 cells transfected with Mesothelin (A431-Meso+). Only minimal adhesion is observed between MUC16 knockdown cells and A431-Meso+ cells. The binding between the MUC16 expressing ovarian tumor cells and the A431-Meso+ cells occurs even in the presence of ascites from patients with ovarian cancer. The strong binding kinetics of the Mesothelin-MUC16 interaction and the cell adhesion between ovarian tumor cells and A431-Meso+ even in the presence of peritoneal fluid strongly support the importance of these two glycoproteins in the peritoneal metastasis of ovarian tumors. The demonstration that N-linked glycans are essential for mediating mesothlein-MUC16 binding may lead to novel therapeutic targets to control the spread of ovarian carcinoma.

  • Mesothelin muc16 binding is a high affinity n glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors
    Molecular Cancer, 2006
    Co-Authors: Jennifer A A Gubbels, Masanori Onda, Tapan K Bera, Jennifer A Belisle, Claudine Rancourt, Martine Migneault, Joseph P Connor, Bangalore K Sathyanarayana, Byungkook Lee, Ira Pastan
    Abstract:

    Background The mucin MUC16 and the glycosylphosphatidylinositol anchored glycoprotein Mesothelin likely facilitate the peritoneal metastasis of ovarian tumors. The biochemical basis and the kinetics of the binding between these two glycoproteins are not clearly understood. Here we have addressed this deficit and provide further evidence supporting the role of the MUC16-Mesothelin interaction in facilitating cell-cell binding under conditions that mimic the peritoneal environment.

Jenette Creaney - One of the best experts on this subject based on the ideXlab platform.

  • pleural fluid Mesothelin as an adjunct to the diagnosis of pleural malignant mesothelioma
    Disease Markers, 2014
    Co-Authors: Jenette Creaney, Ian M Dick, A W Musk, Amanda Segal, Steven J Skates, Nola Olsen, Bruce W S Robinson
    Abstract:

    Rationale. The diagnosis of pleural malignant mesothelioma (MM) by effusion cytology may be difficult and is currently controversial. Effusion Mesothelin levels are increased in patients with MM but the clinical role of this test is uncertain. Objectives. To determine the clinical value of measuring Mesothelin levels in pleural effusion supernatant to aid diagnosis of MM. Methods and Measurements. Pleural effusion samples were collected prospectively from 1331 consecutive patients. Mesothelin levels were determined by commercial ELISA in effusions and their relationship to concurrent pathology reporting and final clinical diagnosis was determined. Results. 2156 pleural effusion samples from 1331 individuals were analysed. The final clinical diagnosis was 183 MM, 436 non-MM malignancy, and 712 nonmalignant effusions. Effusion Mesothelin had a sensitivity of 67% for MM at 95% specificity. Mesothelin was elevated in over 47% of MM cases in effusions obtained before definitive diagnosis of MM was established. In the setting of inconclusive effusion cytology, effusion Mesothelin had a positive predictive value of 79% for MM and 94% for malignancy. Conclusions. A Mesothelin-positive pleural effusion, irrespective of the identification of malignant cells, indicates the likely presence of malignancy and adds weight to the clinical rationale for further investigation to establish a malignant diagnosis.

  • comparison of fibulin 3 and Mesothelin as markers in malignant mesothelioma
    Thorax, 2014
    Co-Authors: Jenette Creaney, Ian M Dick, Tarek Meniawy, Su Lyn Leong, Justine S Leon, Yvonne Demelker
    Abstract:

    Background Pleural malignant mesothelioma (MM) is a deadly tumour predominantly associated with asbestos exposure. A reliable diagnostic and prognostic marker for MM will significantly enhance clinical care and is an area of intense research. Soluble Mesothelin is the most studied and an FDA-approved biomarker for MM. A recent report showed promising results using fibulin-3 as a new diagnostic marker. The aim of this study was to compare the utility of fibulin-3 versus Mesothelin, singly or in combination. Methods Fibulin-3 and soluble Mesothelin were determined by ELISA in the plasma and pleural fluid of 153 patients presenting with a pleural effusion including 82 with MM, 36 with non-MM malignant effusions and 35 with benign effusions. Biomarker concentrations were determined in the plasma of an additional 49 cases with benign asbestos-related disease. Results Mesothelin provides better diagnostic accuracy than fibulin-3 for MM whether measured in plasma or pleural effusion: area under the curve (AUC) for plasma was 0.822 (95% CI 0.76 to 0.87) compared with 0.671 (0.61 to 0.73), respectively, and for pleural fluid AUC was 0.815 (0.74 to 0.87) compared with 0.588 (0.51 to 0.67), respectively. Effusion fibulin-3 was an independent significant prognostic factor for survival in MM patients; HR 2.08 (1.14 to 3.82), p=0.017. MM patients with effusion fibulin-3 levels below the median survived significantly longer than those with levels above the median (14.1 vs 7.9 months, p=0.012). Mesothelin and neutrophil to lymphocyte ratio were not significant prognostic markers. Conclusions Soluble Mesothelin is a superior diagnostic biomarker for MM compared with fibulin-3, whereas fibulin-3 provides superior prognostic information compared with Mesothelin.

  • pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma
    Lung Cancer, 2013
    Co-Authors: Jenette Creaney, Ian M Dick, A W Musk, Bruce W S Robinson, Amanda Segal
    Abstract:

    Abstract Background Malignant mesothelioma (MM), a primarily asbestos-induced tumour, has a poor prognosis, with over-all 5-year survival less than 5%. Tumour biomarkers are being intensely investigated in MM as aids to diagnosis and prognosis. Hyaluronic acid (HA) is produced in MM but its role in prognostication remains uncertain. Materials and methods HA concentrations were determined in matching serum and pleural effusion of 96 MM patients, 26 lung cancer patients and 42 patients with benign effusions resulting from infectious, cardiac, renal, liver and rheumatoid diseases and compared to the current ‘best practice' biomarker, Mesothelin. Liver and kidney function were determined for each patient. Diagnostic accuracy was determined by area under the receiver operator characteristic curve (AUC) analysis following logistic regression modelling. Difference in survival between groups was determined by both log-rank test and Cox proportional hazards regression modelling. Results For effusion HA, the AUC (IQ range) was 0.89 (0.82–0.94) and for effusion Mesothelin, it was 0.85 (0.78–0.90). Serum HA was not diagnostically useful. A combined measure of effusion HA, and serum and effusion Mesothelin had an AUC of 0.92 (0.86–0.96), which was significantly higher than effusion Mesothelin alone. Effusion HA had a biphasic distribution in MM patients, dichotomised at a concentration of 75mg/L. The median survival of MM patients with high effusion HA was 18.0 (13.7–22.4) months, significantly longer than those with low HA effusion levels (12.6 months (8.4–16.8), p =0.004). Serum HA, and effusion and serum Mesothelin were not significant prognostic indicators. Conclusion This study demonstrates that a combined biomarker panel has greater diagnostic accuracy than effusion Mesothelin alone, and that significant prognostic information is provided by effusion HA.

  • serum Mesothelin for diagnosing malignant pleural mesothelioma an individual patient data meta analysis
    Journal of Clinical Oncology, 2012
    Co-Authors: Kevin Hollevoet, Jenette Creaney, Bruce W S Robinson, Johannes B Reitsma, Bogdan Grigoriu, Arnaud Scherpereel, Alfonso Cristaudo, Harvey I Pass, Kristiaan Nackaerts, Jose Rodriguez A Portal
    Abstract:

    Purpose Mesothelin is currently considered the best available serum biomarker of malignant pleural mesothelioma. To examine the diagnostic accuracy and use of serum Mesothelin in early diagnosis, we performed an individual patient data (IPD) meta-analysis. Methods The literature search identified 16 diagnostic studies of serum Mesothelin, measured with the Mesomark enzyme-linked immunosorbent assay. IPD of 4,491 individuals were collected, including several control groups and 1,026 patients with malignant pleural mesothelioma. Mesothelin levels were standardized for between-study differences and age, after which the diagnostic accuracy and the factors affecting it were examined with receiver operating characteristic (ROC) regression analysis. Results At a common diagnostic threshold of 2.00 nmol/L, the sensitivities and specificities of Mesothelin in the different studies ranged widely from 19% to 68% and 88% to 100%, respectively. This heterogeneity can be explained by differences in study population, be...

  • plasma versus serum levels of osteopontin and Mesothelin in patients with malignant mesothelioma which is best
    Lung Cancer, 2011
    Co-Authors: Jenette Creaney, A W Musk, Nicholas De Klerk, Steven J Skates, Deborah Yeoman, Bruce W S Robinson
    Abstract:

    Abstract Background Blood-based markers for malignant mesothelioma (MM), particularly soluble Mesothelin and osteopontin, are currently of great clinical interest. As there is some concern about the sensitivity of osteopontin in serum versus plasma, we compared them in the same patient population to Mesothelin. Methods Soluble Mesothelin and osteopontin concentrations were determined by commercial assays in blood samples from 66 patients with pleural MM, 47 patients with non-malignant asbestos-related lung or pleural disease, 42 patients with other benign pleural and lung diseases and 21 patients with lung cancer. Results Soluble Mesothelin and osteopontin in serum and plasma were significantly elevated in MM patients compared to patients with benign lung and pleural disease. At a level of specificity of 95% relative to patients with benign disease, the sensitivity of Mesothelin in serum and plasma at presentation with symptoms was 67%, and for osteopontin in the plasma was 40% and in the serum was 20% for MM patients. Combining the serum Mesothelin and plasma osteopontin markers using a logistic regression model did not significantly increase the area under the receiver operator curve. Conclusion Plasma osteopontin has a superior diagnostic accuracy to serum. As the choice of blood sample type has limit effect on soluble Mesothelin sensitivity, plasma should be collected for biomarker evaluation in patients suspected of having mesothelioma.

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  • Comprehensive immunohistochemical study of Mesothelin (MSLN) using different monoclonal antibodies 5B2 and MN-1 in 1562 tumors with evaluation of its prognostic value in malignant pleural mesothelioma
    Oncotarget, 2017
    Co-Authors: Shingo Inaguma, Masanori Onda, Zengfeng Wang, Jerzy Lasota, Piotr Czapiewski, Renata Langfort, Janusz Rys, Joanna Szpor, Piotr Waloszczyk, Krzysztof Okoń
    Abstract:

    // Shingo Inaguma 1, 2 , Zengfeng Wang 1 , Jerzy Lasota 1 , Masanori Onda 3 , Piotr Czapiewski 4, 5 , Renata Langfort 6 , Janusz Rys 7 , Joanna Szpor 8 , Piotr Waloszczyk 9 , Krzysztof Okon 8 , Wojciech Biernat 4 , Hiroshi Ikeda 2 , David S. Schrump 10 , Raffit Hassan 10 , Ira Pastan 3 , Markku Miettinen 1 1 Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA 2 Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan 3 Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD, USA 4 Department of Pathomorphology, Medical University of Gdansk, Gdansk, Poland 5 Department of Pathology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany 6 Department of Pathology, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland 7 Department of Tumor Pathology, Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Krakow Branch, Poland 8 Department of Pathomorphology, Jagiellonian University, Krakow, Poland 9 Independent Laboratory of Pathology, Zdunomed, Szczecin, Poland 10 Thoracic and GI Oncology Branch, National Cancer Institute, Bethesda, MD, USA Correspondence to: Shingo Inaguma, email: inaguma@aichi-med-u.ac.jp Keywords: Mesothelin (MSLN), immunohistochemistry, 5B2, MN-1, malignant pleural mesothelioma Received: October 05, 2016      Accepted: February 15, 2017      Published: March 01, 2017 ABSTRACT Mesothelin (MSLN) is a glycophosphatidylinositol (GPI)-linked cell surface protein highly expressed in several types of malignant tumors sometimes in association with increased tumor aggressiveness and poor clinical outcome. In the present study, 1562 tumors were immunohistochemically analyzed for Mesothelin expression using two different types of mouse monoclonal antibodies (5B2 and MN-1) to determine the clinical usefulness of Mesothelin immunohistochemistry as well as to pinpoint potential targets for future anti-Mesothelin therapy. Also, characterization of selected Mesothelin-positive tumors was performed by immunohistochemistry and oncogene sequencing. Among the tumors analyzed, the highest frequencies of Mesothelin-positivity were detected in ovarian serous carcinoma (90% in 5B2 and 94% in MN-1). Both antibodies showed frequent positivity in pancreatic adenocarcinoma (71% using 5B2 and 87% using MN-1) and malignant pleural mesothelioma (75% using 5B2 and 78% using MN-1). In malignant mesothelioma, overall survival was significantly longer in the cohort of patients with diffuse membranous expression of Mesothelin ( P < 0.001). Both antibodies showed positive staining in thymic carcinoma (77% in 5B2 and 59% in MN-1), however, no expression was detected in thymoma. No correlation was detected between Mesothelin expression and mismatch repair system deficient phenotype or gene mutation ( BRAF and RAS ) status in gastrointestinal adenocarcinomas. Mesothelin immunohistochemistry may assist the differential diagnosis of thymoma vs. thymic carcinoma as well as prognostication of mesothelioma patients. Our results demonstrate that patients with solid tumors expressing Mesothelin could be targeted by anti-Mesothelin therapies.

  • Mesothelin expression in human lung cancer
    Clinical Cancer Research, 2007
    Co-Authors: Tapan K Bera, Raffit Hassan, Masanori Onda, Mark C Willingham, David J Fitzgerald, Ira Pastan
    Abstract:

    Purpose: To investigate Mesothelin as a new target for immunotherapy in lung cancer. Experimental Design: Mesothelin mRNA and protein expression were assessed by reverse transcription-PCR, immunoblotting, and immunohistochemistry in human lung cancer specimens. Expression was also characterized in human lung cancer cell lines by flow cytometry and immunoblotting. The SS1P immunotoxin specific for Mesothelin was assessed for its cytotoxic activity against lung cancer cells. Results: We found that Mesothelin mRNA was expressed in 83% of lung adenocarcinomas (10 of 12 patients). The Mesothelin precursor protein was detected in 82% of lung adenocarcinoma (9 of 11 patients), and its mature form was detected in 55% (6 of 11 patients). Immunohistochemistry showed strong and diffuse Mesothelin staining in human lung adenocarcinomas and weak or modest staining in squamous cell carcinomas. We detected Mesothelin mRNA in 78% of lung cancer cell lines (7 of 9) of the NCI-60 cell line panel. Mesothelin mRNA and proteins were expressed at a high level in non–small cell lung cancer lines EKVX, NCI-H460, NCI-H322M, and NCI-H522. Flow cytometric analysis showed high surface expression of Mesothelin in NCI-H322M and EKVX cell lines. Immunotoxin SS1P showed high cytotoxic activity on NCI-H322M and EKVX cells with IC 50 values ranging from 2 to 5 ng/mL. Conclusions: Mesothelin is expressed on the surface of most lung adenocarcinoma cells. Immunotoxin SS1P is cytotoxic against Mesothelin-expressing lung cancer cell lines and merits evaluation as a new therapeutic agent in treating non–small cell lung cancer.

  • Mesothelin muc16 binding is a high affinity n glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors
    Molecular Cancer, 2006
    Co-Authors: Jennifer A A Gubbels, Masanori Onda, Tapan K Bera, Jennifer A Belisle, Claudine Rancourt, Martine Migneault, Joseph P Connor, Bangalore K Sathyanarayana, Byungkook Lee, Ira Pastan
    Abstract:

    The mucin MUC16 and the glycosylphosphatidylinositol anchored glycoprotein Mesothelin likely facilitate the peritoneal metastasis of ovarian tumors. The biochemical basis and the kinetics of the binding between these two glycoproteins are not clearly understood. Here we have addressed this deficit and provide further evidence supporting the role of the MUC16-Mesothelin interaction in facilitating cell-cell binding under conditions that mimic the peritoneal environment. In this study we utilize recombinant-Fc tagged human Mesothelin to measure the binding kinetics of this glycoprotein to MUC16 expressed on the ovarian tumor cell line OVCAR-3. OVCAR-3 derived sublines that did not express MUC16 showed no affinity for Mesothelin. In a flow cytometry-based assay Mesothelin binds with very high affinity to the MUC16 on the OVCAR-3 cells with an apparent Kd of 5–10 nM. Maximum interaction occurs within 5 mins of incubation of the recombinant Mesothelin with the OVCAR-3 cells and significant binding is observed even after 10 sec. A five-fold molar excess of soluble MUC16 was unable to completely inhibit the binding of Mesothelin to the OVCAR-3 cells. Oxidation of the MUC16 glycans, removal of its N-linked oligosaccharides, and treatment of the mucin with wheat germ agglutinin and erythroagglutinating phytohemagglutinin abrogates its binding to Mesothelin. These observations suggest that at least a subset of the MUC16-asscociated N-glycans is required for binding to Mesothelin. We also demonstrate that MUC16 positive ovarian tumor cells exhibit increased adherence to A431 cells transfected with Mesothelin (A431-Meso+). Only minimal adhesion is observed between MUC16 knockdown cells and A431-Meso+ cells. The binding between the MUC16 expressing ovarian tumor cells and the A431-Meso+ cells occurs even in the presence of ascites from patients with ovarian cancer. The strong binding kinetics of the Mesothelin-MUC16 interaction and the cell adhesion between ovarian tumor cells and A431-Meso+ even in the presence of peritoneal fluid strongly support the importance of these two glycoproteins in the peritoneal metastasis of ovarian tumors. The demonstration that N-linked glycans are essential for mediating mesothlein-MUC16 binding may lead to novel therapeutic targets to control the spread of ovarian carcinoma.

  • Mesothelin muc16 binding is a high affinity n glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors
    Molecular Cancer, 2006
    Co-Authors: Jennifer A A Gubbels, Masanori Onda, Tapan K Bera, Jennifer A Belisle, Claudine Rancourt, Martine Migneault, Joseph P Connor, Bangalore K Sathyanarayana, Byungkook Lee, Ira Pastan
    Abstract:

    Background The mucin MUC16 and the glycosylphosphatidylinositol anchored glycoprotein Mesothelin likely facilitate the peritoneal metastasis of ovarian tumors. The biochemical basis and the kinetics of the binding between these two glycoproteins are not clearly understood. Here we have addressed this deficit and provide further evidence supporting the role of the MUC16-Mesothelin interaction in facilitating cell-cell binding under conditions that mimic the peritoneal environment.

  • detection and quantitation of serum Mesothelin a tumor marker for patients with mesothelioma and ovarian cancer
    Clinical Cancer Research, 2006
    Co-Authors: Raffit Hassan, Ira Pastan, Jingli Zhang, Mark C Willingham, Alan T Remaley, Maureen Sampson, Derrick D Cox, James F Pingpank, Richard B Alexander, Masanori Onda
    Abstract:

    Purpose: To determine whether Mesothelin, a cell surface protein highly expressed in mesothelioma and ovarian cancer, is shed into serum and if so to accurately measure it. Experimental Design: We developed a sandwich ELISA using antibodies reacting with two different epitopes on human Mesothelin. To quantitate serum Mesothelin levels, a standard curve was generated using a Mesothelin-Fc fusion protein. Sera from 24 healthy volunteers, 95 random hospital patients, 56 patients with mesothelioma, and 21 patients with ovarian cancer were analyzed. Serum Mesothelin levels were also measured before and after surgical cytoreduction in six patients with peritoneal mesothelioma. Results: Elevated serum Mesothelin levels were noted in 40 of 56 (71%) patients with mesothelioma and in 14 of 21 (67%) patients with ovarian cancer. Serum Mesothelin levels were increased in 80% and 75% of the cases of mesothelioma and ovarian cancer, respectively, in which the tumors expressed Mesothelin by immunohistochemistry. Out of the six patients with peritoneal mesothelioma who underwent surgery, four had elevated serum Mesothelin levels before surgery. Out of these four patients, three had cytoreductive surgery and the serum Mesothelin level decreased by 71% on postoperative day 1 and was undetectable by postoperative day 7. Conclusions: We developed a serum Mesothelin assay that shows that Mesothelin is elevated in patients with mesothelioma and ovarian cancer. The rapid decrease in Mesothelin levels after surgery in patients with peritoneal mesothelioma suggests that serum Mesothelin may be a useful test to monitor treatment response in Mesothelin-expressing cancers.