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Hagerty BL, Sato T, Wu R, Ishikawa T, Takabe K. Mesothelin (MSLN) is Highly Expressed in Triple Negative Breast Cancer and is Associated with Enhanced Cell Proliferation and Proinflammatory Tumor Microenvironment. Ann Surg Oncol 2025; 32:4476-4486. [PMID: 40080368 DOI: 10.1245/s10434-025-17117-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/18/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Mesothelin (MSLN), a cell surface glycoprotein, is commonly expressed in several cancers, including 40% of triple negative breast cancer (TNBC) cases. Although its cellular or physiologic functions remain unclear, MSLN has been leveraged as a target for molecular therapies. This study investigates MSLN's potential role in TNBC, the breast cancer (BC) subtype with poorest outcomes. PATIENTS AND METHODS The breast cancer (BC) cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 313), The Cancer Genome Atlas (TCGA, n = 160), and SCAN-B (n = 155) were used to obtain biological variables and gene expression data. RESULTS High MSLN expression was primarily observed in epithelial cells, and its expression was associated with reduced stromal adipocytes in the tumor microenvironment (TME), supporting its role as a TNBC surface marker. MSLN expression was also associated with the TNBC subtype and advanced N stages in BC. However, MSLN expression did not correlate with long-term survival outcomes, including overall survival (OS), disease-specific survival (DSS), or disease-free survival (DFS); nevertheless, it was still associated with favorable response to neoadjuvant chemotherapy (NAC). Indeed, MSLN-high tumors exhibited a proinflammatory microenvironment, higher cancer-testis antigen (CTA) scores, and increased immune cell activity, notably immature dendritic cells (iDCs) and M1 macrophages. Biologically, MSLN expression was linked to increased cellular proliferation, with gene set enrichment analysis (GSEA) showing enrichment in pathways related to rapid proliferation, such as G2M checkpoint and E2F targets. CONCLUSIONS MSLN-high TNBC is characterized by increased tumor grade, enhanced cell proliferation, and a proinflammatory microenvironment, showing better response to neoadjuvant chemotherapy without significant impact on long-term survival outcomes.
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Affiliation(s)
- Brendan L Hagerty
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Takumi Sato
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan.
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA.
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan.
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2
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Soucy AM, Brune JE, Jayaraman A, Shenoy AT, Korkmaz FT, Etesami NS, Hiller BE, Martin IM, Goltry WN, Ha CT, Crossland NA, Campbell JD, Beach TG, Traber KE, Jones MR, Quinton LJ, Bosmann M, Frevert CW, Mizgerd JP. Transcriptomic responses of lung mesenchymal cells during pneumonia. JCI Insight 2025; 10:e177084. [PMID: 39998887 PMCID: PMC11981624 DOI: 10.1172/jci.insight.177084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/18/2025] [Indexed: 02/27/2025] Open
Abstract
The role of mesenchymal cells during respiratory infection is not well defined, including whether, which, and how the different types of mesenchymal cells respond. We collected all mesenchymal cells from lung single-cell suspensions of mice that were naive (after receiving only saline vehicle), pneumonic (after intratracheal instillation of pneumococcus 24 hours previously), or resolved from infection (after nonlethal pneumococcal infections 6 weeks previously) and performed single-cell RNA sequencing. Cells clustered into 5 well-separated groups based on their transcriptomes: matrix fibroblasts, myofibroblasts, pericytes, smooth muscle cells, and mesothelial cells. Fibroblasts were the most abundant and could be further segregated into Pdgfra+Npnt+Ces1d+Col13a1+ alveolar fibroblasts and Cd9+Pi16+Sca1+Col14a1+ adventitial fibroblasts. The cells from naive and resolved groups overlapped in dimension reduction plots, suggesting the mesenchymal cells returned to baseline transcriptomes after resolution. During pneumonia, all mesenchymal cells responded with altered transcriptomes, revealing a core response that had been conserved across cell types as well as distinct mesenchymal cell type-specific responses. The different subsets of fibroblasts induced similar gene sets, but the alveolar fibroblasts responded more strongly than the adventitial fibroblasts. These data demonstrated diverse and specialized immune activities of lung mesenchymal cells during pneumonia.
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Affiliation(s)
- Alicia M. Soucy
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Jourdan E. Brune
- Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington, USA
- Center for Lung Biology, University of Washington, Seattle, Washington, USA
| | - Archana Jayaraman
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Anukul T. Shenoy
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Filiz T. Korkmaz
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Neelou S. Etesami
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Bradley E. Hiller
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Ian M.C. Martin
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Wesley N. Goltry
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Catherine T. Ha
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Nicholas A. Crossland
- National Emerging Infectious Diseases Laboratory, Boston University, Boston, Massachusetts, USA
- Department of Pathology and Laboratory Medicine
- Department of Virology, Immunology, & Microbiology; and
| | - Joshua D. Campbell
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Thomas G. Beach
- Banner Sun Health Research Institute Brain and Body Donation Program, Sun City, Arizona, USA
| | - Katrina E. Traber
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Matthew R. Jones
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Lee J. Quinton
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Markus Bosmann
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Charles W. Frevert
- Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington, USA
- Center for Lung Biology, University of Washington, Seattle, Washington, USA
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, Washington, USA
| | - Joseph P. Mizgerd
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Department of Virology, Immunology, & Microbiology; and
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Department of Biochemistry and Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
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Chen Q, Sun Y, Li H. Application of CAR-T cell therapy targeting mesothelin in solid tumor treatment. Discov Oncol 2024; 15:289. [PMID: 39023820 PMCID: PMC11258118 DOI: 10.1007/s12672-024-01159-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024] Open
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy is one of the most effective immunotherapies. CAR-T-cell therapy has achieved great success in the treatment of hematological malignancies. However, due to the characteristics of solid malignant tumors, such as on-target effects, off-tumor toxicity, an immunosuppressive tumor microenvironment (TME), and insufficient trafficking, CAR-T-cell therapy for solid tumors is still in the exploration stage. Mesothelin (MSLN) is a molecule expressed on the surface of various solid malignant tumor cells that is suitable as a target of tumor cells with high MSLN expression for CAR-T-cell therapy. This paper briefly described the development of CAR-T cell therapy and the structural features of MSLN, and especially summarized the strategies of structure optimization of MSLN-targeting CAR-T-cells and the enhancement methods of MSLN-targeting CAR-T cell anti-tumor efficacy by summarizing some preclinical experiment and clinical trials. When considering MSLN-targeting CAR-T-cell therapy as an example, this paper summarizes the efforts made by researchers in CAR-T-cell therapy for solid tumors and summarizes feasible treatment plans by integrating the existing research results.
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Affiliation(s)
- Qiuhong Chen
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, No. 88 East Wenhua Road, Jinan, 250014, People's Republic of China
| | - Yang Sun
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, No. 88 East Wenhua Road, Jinan, 250014, People's Republic of China
| | - Hua Li
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, No. 88 East Wenhua Road, Jinan, 250014, People's Republic of China.
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Sorino C, Mondoni M, Marchetti G, Agati S, Inchingolo R, Mei F, Flamini S, Lococo F, Feller-Kopman D. Pleural Mesothelioma: Advances in Blood and Pleural Biomarkers. J Clin Med 2023; 12:7006. [PMID: 38002620 PMCID: PMC10672377 DOI: 10.3390/jcm12227006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/30/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Pleural mesothelioma (PM) is a type of cancer that is highly related to exposure to asbestos fibers. It shows aggressive behavior, and the current therapeutic approaches are usually insufficient to change the poor prognosis. Moreover, apart from staging and histological classification, there are no validated predictors of its response to treatment or its long-term outcomes. Numerous studies have investigated minimally invasive biomarkers in pleural fluid or blood to aid in earlier diagnosis and prognostic assessment of PM. The most studied marker in pleural effusion is mesothelin, which exhibits good specificity but low sensitivity, especially for non-epithelioid PM. Other biomarkers found in pleural fluid include fibulin-3, hyaluronan, microRNAs, and CYFRA-21.1, which have lower diagnostic capabilities but provide prognostic information and have potential roles as therapeutic targets. Serum is the most investigated matrix for biomarkers of PM. Several serum biomarkers in PM have been studied, with mesothelin, osteopontin, and fibulin-3 being the most often tested. A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker in patients with suspected mesothelioma. With different serum and pleural fluid cut-offs, it provides useful information on the diagnosis, prognosis, follow-up, and response to therapy in epithelioid PM. Panels combining different markers and proteomics technologies show promise in terms of improving clinical performance in the diagnosis and monitoring of mesothelioma patients. However, there is still no evidence that early detection can improve the treatment outcomes of PM patients.
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Affiliation(s)
- Claudio Sorino
- Division of Pulmonology, Sant’Anna Hospital of Como, University of Insubria, 21100 Varese, Italy; (C.S.); (S.A.)
| | - Michele Mondoni
- Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, Università degli Studi di Milano, 20122 Milan, Italy
| | | | - Sergio Agati
- Division of Pulmonology, Sant’Anna Hospital of Como, University of Insubria, 21100 Varese, Italy; (C.S.); (S.A.)
| | - Riccardo Inchingolo
- Pulmonary Medicine Unit, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Federico Mei
- Respiratory Diseases Unit, Department of Internal Medicine, Azienda Ospedaliero Universitaria delle Marche, 60126 Ancona, Italy;
| | - Sara Flamini
- Departement of Thoracic Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (S.F.); (F.L.)
- Thoracic Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Filippo Lococo
- Departement of Thoracic Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (S.F.); (F.L.)
- Thoracic Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - David Feller-Kopman
- Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA;
- Division of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA
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5
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Zhu Y, Zuo D, Wang K, Lan S, He H, Chen L, Chen X, Feng M. Mesothelin-targeted CAR-T therapy combined with irinotecan for the treatment of solid cancer. J Cancer Res Clin Oncol 2023; 149:15027-15038. [PMID: 37612388 DOI: 10.1007/s00432-023-05279-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/10/2023] [Indexed: 08/25/2023]
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cell therapy has shown promising results in treating blood cancers, but it has limited efficacy against solid tumors that express mesothelin (MSLN). One of the reasons is the immunosuppressive tumor microenvironment, which consists of physical barriers, multiple mechanisms of immune evasion, and various biochemical factors that favor tumor growth and survival. These factors reduce the antitumor activity of MSLN-targeted CAR T cells in clinical trials. Therefore, new therapeutic strategies are needed to enhance the effectiveness of MSLN-targeted CAR T cell therapy. METHODS To investigate whether the antitumor efficacy of anti-MSLN CAR-T cells depends on the epitopes they recognize, we generated MSLN-targeted CAR T cells that bind to different regions of MSLN (Region I, II, III and Full length). We then evaluated the antitumor activity of MSLN-targeted CAR T cells alone or in combination with the chemotherapeutic drug irinotecan or an anti-PD-1 antibody in vitro and in vivo. RESULTS We found that MSLN-targeted CAR T cells effectively killed MSLN-positive cancer cells (H9, H226 and Panc-1), but not MSLN-negative cells (A431) in vitro. In a mouse model of H9 tumor xenografts, all CAR T cells showed similar tumor suppression, but an MSLN-targeted scFv with Region I epitope, R47, performed slightly better. Combining irinotecan with CAR_R47 T cells enhanced tumor control synergistically in both H9 xenograft mice and patient-derived xenograft mice. CONCLUSIONS Our results suggest that irinotecan can enhance the antitumor activity of MSLN-targeted CAR T cells, and offer a promising combination therapy strategy for MSLN-positive solid tumors.
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Affiliation(s)
- Yuankui Zhu
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Dianbao Zuo
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Ke Wang
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Sina Lan
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Huixia He
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Liu Chen
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Xin Chen
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
| | - Mingqian Feng
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
- College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
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Hagerty BL, Takabe K. Biology of Mesothelin and Clinical Implications: A Review of Existing Literature. World J Oncol 2023; 14:340-349. [PMID: 37869242 PMCID: PMC10588497 DOI: 10.14740/wjon1655] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/30/2023] [Indexed: 10/24/2023] Open
Abstract
Since its discovery in 1992, mesothelin (MSLN) has generated significant interest as a therapeutic target. A number of characteristics make it ideal for this purpose. First, it is not expressed on the parenchyma of any vital organs. Second, it is differentially expressed on a number of cancer types that have relatively poor prognosis and lack effective systemic options. Third, it is expressed on the cell membrane making it accessible to large molecule targeted therapies. However, unlike other drug targets that have been exploited for therapeutic benefit, the precise function of MSLN, why it is expressed in certain cancers, and its biological role have not been clearly elucidated. Here the existing literature on the cellular function and expression patterns of MSLN across tumor types is reviewed in order to gain further understanding of this intriguing molecule. In doing so, we conclude that there remains significant ambiguity surrounding its function and role in cellular and tumor biology. Furthermore, the expression of MSLN and its relation of prognosis seems to depend on the type of tumor. Finally, the unified mechanism by which MSLN acts as a protein that conveys tumor aggressiveness remains elusive. What is clear is that there is much yet to be discovered in this realm and doing so may have large implications for treatment of otherwise lethal malignancies.
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Affiliation(s)
- Brendan L Hagerty
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan
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7
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Deiana C, Fabbri F, Tavolari S, Palloni A, Brandi G. Improvements in Systemic Therapies for Advanced Malignant Mesothelioma. Int J Mol Sci 2023; 24:10415. [PMID: 37445594 DOI: 10.3390/ijms241310415] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/05/2023] [Accepted: 06/14/2023] [Indexed: 07/15/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy associated with poor prognosis and a 5-year survival rate of 12%. Many drugs have been tested over the years with conflicting results. The aim of this review is to provide an overview of current therapies in MPM and how to best interpret the data available on these drugs. Furthermore, we focused on promising treatments under investigation, such as immunotherapy with targets different from anti-PD-1/PD-L1 inhibitors, vaccines, target therapies, and metabolism-based strategies.
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Affiliation(s)
- Chiara Deiana
- Medical Oncology, IRCCS Azienda Ospedaliera, Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Francesca Fabbri
- Medical Oncology, IRCCS Azienda Ospedaliera, Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Simona Tavolari
- Medical Oncology, IRCCS Azienda Ospedaliera, Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Andrea Palloni
- Medical Oncology, IRCCS Azienda Ospedaliera, Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliera, Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
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8
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He Q, Hu H, Yang F, Song D, Zhang X, Dai X. Advances in chimeric antigen receptor T cells therapy in the treatment of breast cancer. Biomed Pharmacother 2023; 162:114609. [PMID: 37001182 DOI: 10.1016/j.biopha.2023.114609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
Breast cancer (BC) is the most frequently occurring cancer type seriously threatening the lives of women worldwide. Clinically, the high frequency of diverse resistance to current therapeutic strategies advocates a demand to develop novel and effective approaches for the efficient treatment of BC. The chimeric antigen receptor T (CAR-T) cells therapy, one of the immunotherapies, has displayed powerful capacity to specifically kill and eliminate tumors. Due to the success of CAR-T therapy achieved in treating hematological malignancy, the effect of CAR-T cells therapy has been tested in various human diseases including breast cancer. This review summarized and discussed the landscape of the CAR-T therapy for breast cancer, including the advances, challenge and countermeasure of CAR-T therapy in research and clinical application. The roles of potential antigen targets, tumor microenvironment, immune escape in regulating CAR-T therapy, the combination of CAR-T therapy with other therapeutic strategies to further enhance therapeutic efficacy of CAR-T treatment were also highlighted. Therefore, our review provided a comprehensive understanding of CAR-T cell therapy in breast cancer which will awake huge interests for future in-depth investigation of CAR-T based therapy in cancer treatment.
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9
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Zhai X, Mao L, Wu M, Liu J, Yu S. Challenges of Anti-Mesothelin CAR-T-Cell Therapy. Cancers (Basel) 2023; 15:cancers15051357. [PMID: 36900151 PMCID: PMC10000068 DOI: 10.3390/cancers15051357] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/10/2023] [Accepted: 02/06/2023] [Indexed: 02/23/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy is a kind of adoptive T-cell therapy (ACT) that has developed rapidly in recent years. Mesothelin (MSLN) is a tumor-associated antigen (TAA) that is highly expressed in various solid tumors and is an important target antigen for the development of new immunotherapies for solid tumors. This article reviews the clinical research status, obstacles, advancements and challenges of anti-MSLN CAR-T-cell therapy. Clinical trials on anti-MSLN CAR-T cells show that they have a high safety profile but limited efficacy. At present, local administration and introduction of new modifications are being used to enhance proliferation and persistence and to improve the efficacy and safety of anti-MSLN CAR-T cells. A number of clinical and basic studies have shown that the curative effect of combining this therapy with standard therapy is significantly better than that of monotherapy.
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Affiliation(s)
- Xuejia Zhai
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing 400038, China
| | - Ling Mao
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing 400038, China
| | - Min Wu
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing 400038, China
| | - Jie Liu
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing 400038, China
| | - Shicang Yu
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing 400038, China
- Jinfeng Laboratory, Chongqing 401329, China
- Correspondence:
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10
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Weidemann S, Gorbokon N, Lennartz M, Hube-Magg C, Fraune C, Bernreuther C, Clauditz TS, Jacobsen F, Jansen K, Schmalfeldt B, Wölber L, Paluchowski P, Berkes E, Heilenkötter U, Sauter G, Uhlig R, Wilczak W, Steurer S, Simon R, Krech T, Marx A, Burandt E, Lebok P. High Homogeneity of Mesothelin Expression in Primary and Metastatic Ovarian Cancer. Appl Immunohistochem Mol Morphol 2023; 31:77-83. [PMID: 36728364 PMCID: PMC9928564 DOI: 10.1097/pai.0000000000001097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/22/2022] [Indexed: 02/03/2023]
Abstract
To study the extent of heterogeneity of mesothelin overexpression in primary ovarian cancers and their peritoneal and lymph node metastases, a tissue microarray (TMA) was constructed from multiple sites of 220 ovarian cancers and analyzed by immunohistochemistry. One tissue core each was taken from up to 18 different tumor blocks per cancer, resulting in a total of 2460 tissue spots from 423 tumor sites (188 primary cancers, 162 peritoneal carcinosis, and 73 lymph node metastases). Positive mesothelin expression was found in 2041 of the 2342 (87%) arrayed tissue spots and in 372 of the 392 (95%) tumor sites that were interpretable for mesothelin immunohistochemistry. Intratumoral heterogeneity was found in 23% of 168 primary cancer sites interpretable for mesothelin and decreased to 12% in 154 peritoneal carcinosis and to 6% in 71 lymph node metastases ( P <0.0001). Heterogeneity between the primary tumor and matched peritoneal carcinosis was found in 16% of 102 cancers with interpretable mesothelin results. In these cancers, the mesothelin status switched from positive in the primary tumor to negative in the peritoneal carcinosis (3 cancers) in or vice versa (2 cancers), or a mixture of positive and negative peritoneal carcinoses was found (11 cancers). No such switch was seen between the mesothelin-interpretable primary tumors and their nodal metastases of 59 cancers, and only 1 mesothelin-positive tumor had a mixture of positive and negative lymph node metastases. In conclusion, mesothelin expression is frequent and highly homogeneous in ovarian cancer.
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Affiliation(s)
- Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | | | | | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | | | - Till S. Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Kristina Jansen
- General, Visceral and Thoracic Surgery Department and Clinic
| | | | - Linn Wölber
- Department of Gynecology, University Medical Center Hamburg-Eppendorf
| | | | - Enikö Berkes
- Department of Gynecology, Regio Clinic Itzehoe, Itzehoe
| | | | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
- Clinical Center Osnabrueck, Institute of Pathology, Osnabrueck
| | - Andreas Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
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11
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Perera ND, Mansfield AS. The Evolving Therapeutic Landscape for Malignant Pleural Mesothelioma. Curr Oncol Rep 2022; 24:1413-1423. [PMID: 35657483 PMCID: PMC9613518 DOI: 10.1007/s11912-022-01302-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2022] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW For patients with malignant pleural mesothelioma, prognosis is poor with extremely low 5-year survival rates and limited therapeutic options. Here, we review the current treatment landscape for mesothelioma and highlight promising future therapeutic directions. RECENT FINDINGS Evolving frontline therapeutic options for mesothelioma include VEGF inhibition in combination with chemotherapy and dual immune checkpoint inhibition, with synergisms between the therapies and response prediction via biomarkers also being explored. Evolving experimental treatments for mesothelioma include PARP and ALK inhibitors, dendritic and CAR T-cell therapies, anti-mesothelin vaccines, and oncolytic viral therapies, representing timely advances in the field. The therapeutic landscape for malignant pleural mesothelioma is evolving and preferred treatment in the frontline and later settings will likely evolve with it. However, this does not preclude the evidence for including multi-modal therapies spanning angiogenesis and immune checkpoint inhibitors, and biomarker utilization, in current clinical trials and management.
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Affiliation(s)
- Nirosha D Perera
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Aaron S Mansfield
- Division of Medical Oncology, Mayo Clinic, 200 First Street Southwest, Rochester, MN, 55905, USA.
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12
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Systematic Review, Meta-Analysis and Bioinformatic Analysis of Biomarkers for Prognosis of Malignant Pleural Mesothelioma. Diagnostics (Basel) 2022; 12:diagnostics12092210. [PMID: 36140611 PMCID: PMC9497920 DOI: 10.3390/diagnostics12092210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 08/29/2022] [Accepted: 09/09/2022] [Indexed: 11/17/2022] Open
Abstract
In previous studies, non-invasive diagnostic biomarkers showed great benefit in the early-stage diagnosis of malignant pleural mesothelioma (MPM). However, the accuracy of different biomarkers was controversial. In this study, meta-analysis and bioinformatics analysis were conducted to compare the accuracy of the following three biomarkers and explore the relationship between the gene expression levels and MPM. A systematic search of meta-analysis was conducted using PubMed, EMBASE and Cochrane Library to identify relevant studies from the inception to March 2021. QUADAS-2 for Quality Assessment of Diagnostic Accuracy Studies was used to evaluate the quality of eligible studies. The meta-analysis was performed utilizing Stata 15.0 and Review Manager 5.4 software. The meta-analysis results showed that 31 studies that involved 8750 participants were included. The pooled sensitivity and specificity (SPE) were 0.90 (95% CI: 0.74, 0.97) and 0.91 (95% CI: 0.84, 0.95) for Fibulin-3, 0.66 (95% CI, 0.51–0.78) and 0.91 (95% CI, 0.82–0.96) for mesothelin (MSLN), 0.68 (95% CI: 0.63,0.73) and 0.86 (95% CI: 0.82,0.90) for soluble mesothelin-related peptides (SMRP), and 0.74 (95% CI, 0.66-0.80) and 0.89 (95% CI, 0.85–0.91) for MSLN + SMRP + Fibulin-3. Compared with the other two biomarkers, Fibulin-3 may be more appropriate to be one of the indicators for combined diagnosis. Bioinformatics analysis showed that the low expression level of the MSLN gene was significantly related to longer survival time and better prognosis of MPM patients. However, considering the limitation in the quality and sample size of the included research, further studies are required.
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13
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Lopci E, Castello A, Mansi L. FDG PET/CT for Staging and Restaging Malignant Mesothelioma. Semin Nucl Med 2022; 52:806-815. [PMID: 35965111 DOI: 10.1053/j.semnuclmed.2022.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 07/19/2022] [Accepted: 07/25/2022] [Indexed: 11/11/2022]
Abstract
Malignant mesothelioma is an aggressive tumor originating from the mesothelial cells and presenting in general with a very poor prognosis. The pleural localization represents the prevailing disease site, while peritoneal involvement is commonly rare. The WHO classifies mesotheliomas into epithelioid, biphasic, and sarcomatoid histotypes, having diverse outcome with the sarcomatoid or biphasic forms showing the poorest prognosis. Given the peculiar rind-like pattern of growth, mesothelioma assessment is rather challenging for medical imagers. Conventional imaging is principally based on contrast-enhanced CT, while the role of functional and metabolic imaging is regarded as complementary. By focusing essentially on the staging and restaging role of [18F]FDG PET/CT in malignant mesotheliomas, the present review will summarize the available data present in literature and provide some hints on alternative imaging and future perspectives. Given the prevailing incidence of pleural disease, the majority of the information will be addressed on malignant pleural mesothelioma, although a summary of principal characteristics and imaging findings in patients with peritoneal mesothelioma will be also provided.
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Affiliation(s)
- Egesta Lopci
- Nuclear Medicine Unit, IRCCS - Humanitas Research Hospital, Milan, Italy.
| | - Angelo Castello
- Nuclear Medicine Unit, Fondazione IRCCS Ca' Granda, Milan, Italy
| | - Luigi Mansi
- Interuniversity Research Center for the Sustainable Development (CIRPS), Rome, Italy
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14
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Furumoto H, Kato T, Wakiyama H, Furusawa A, Choyke PL, Kobayashi H. Endoscopic Applications of Near-Infrared Photoimmunotherapy (NIR-PIT) in Cancers of the Digestive and Respiratory Tracts. Biomedicines 2022; 10:846. [PMID: 35453596 PMCID: PMC9027987 DOI: 10.3390/biomedicines10040846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/11/2022] Open
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and promising therapy that specifically destroys target cells by irradiating antibody-photo-absorber conjugates (APCs) with NIR light. APCs bind to target molecules on the cell surface, and when exposed to NIR light, cause disruption of the cell membrane due to the ligand release reaction and dye aggregation. This leads to rapid cell swelling, blebbing, and rupture, which leads to immunogenic cell death (ICD). ICD activates host antitumor immunity, which assists in killing still viable cancer cells in the treated lesion but is also capable of producing responses in untreated lesions. In September 2020, an APC and laser system were conditionally approved for clinical use in unresectable advanced head and neck cancer in Japan, and are now routine in appropriate patients. However, most tumors have been relatively accessible in the oral cavity or neck. Endoscopes offer the opportunity to deliver light deeper within hollow organs of the body. In recent years, the application of endoscopic therapy as an alternative to surgery for the treatment of cancer has expanded, providing significant benefits to inoperable patients. In this review, we will discuss the potential applications of endoscopic NIR-PIT, especially in thoracic and gastrointestinal cancers.
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Affiliation(s)
| | | | | | | | | | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (H.F.); (T.K.); (H.W.); (A.F.); (P.L.C.)
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15
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Davis A, Ke H, Kao S, Pavlakis N. An Update on Emerging Therapeutic Options for Malignant Pleural Mesothelioma. LUNG CANCER (AUCKLAND, N.Z.) 2022; 13:1-12. [PMID: 35264891 PMCID: PMC8900635 DOI: 10.2147/lctt.s288535] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 02/10/2022] [Indexed: 12/11/2022]
Abstract
The treatment paradigm for malignant pleural mesothelioma (MPM) has changed little in the last 18 years. Radical intent treatment, consisting of surgical resection, radiotherapy and chemotherapy, has been offered to a highly select few; however, there is little randomised evidence to validate this approach. Prior to 2020 chemotherapy with platinum and an anti-folate was the only intervention with randomised evidence to demonstrate improved overall survival (OS) in MPM. No systemic therapy had been demonstrated to improve OS in the second line setting until 2020. The publication of the Checkmate 743 trial in 2021 demonstrated a survival benefit of combination immunotherapy over standard chemotherapy in newly diagnosed patients with MPM. This finding was shortly followed by the CONFIRM trial which demonstrates a modest but significant survival benefit of second line nivolumab versus placebo in patients having previously received standard chemotherapy. The results of these trials, recent biomarker directed therapy and chemotherapy adjuncts are discussed within this review. The integration of immunotherapy for the few patients in whom radical surgical therapy is intended is currently the subject of clinical trials and offers the prospect of improving outcomes in this rare but devastating disease.
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Affiliation(s)
- Alexander Davis
- Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia.,Department of Medical Oncology, Western Cancer Centre, Dubbo, NSW, Australia
| | - Helen Ke
- Asbestos Diseases Research Institute, Rhodes, NSW, Australia
| | - Steven Kao
- Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia.,Asbestos Diseases Research Institute, Rhodes, NSW, Australia.,School of Medicine, University of Sydney, Camperdown, NSW, Australia
| | - Nick Pavlakis
- School of Medicine, University of Sydney, Camperdown, NSW, Australia.,Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.,Department of Medical Oncology, Genesis Care, St Leonards, NSW, Australia
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16
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Obacz J, Yung H, Shamseddin M, Linnane E, Liu X, Azad AA, Rassl DM, Fairen-Jimenez D, Rintoul RC, Nikolić MZ, Marciniak SJ. Biological basis for novel mesothelioma therapies. Br J Cancer 2021; 125:1039-1055. [PMID: 34226685 PMCID: PMC8505556 DOI: 10.1038/s41416-021-01462-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/13/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.
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Affiliation(s)
- Joanna Obacz
- Cambridge Institute for Medical Research, Keith Peters Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Henry Yung
- UCL Respiratory, Division of Medicine Rayne Institute, University College London, London, UK
| | - Marie Shamseddin
- Wellcome Sanger Institute, Wellcome Trust Genome Campus, Saffron Walden, UK
| | - Emily Linnane
- Adsorption & Advanced Materials Laboratory, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Xiewen Liu
- Adsorption & Advanced Materials Laboratory, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Arsalan A Azad
- Cambridge Institute for Medical Research, Keith Peters Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Doris M Rassl
- Department of Histopathology, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK
| | - David Fairen-Jimenez
- Adsorption & Advanced Materials Laboratory, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Robert C Rintoul
- Department of Oncology, University of Cambridge, Cambridge, UK
- Department of Thoracic Oncology, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK
| | - Marko Z Nikolić
- UCL Respiratory, Division of Medicine Rayne Institute, University College London, London, UK
| | - Stefan J Marciniak
- Cambridge Institute for Medical Research, Keith Peters Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
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17
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Kunk PR, Dougherty SC, Lynch K, Whitehair R, Meneveau M, Obeid JM, Winters K, Ju JY, Stelow EB, Bauer TW, Slingluff CL, Rahma OE. Myeloid Cell Infiltration Correlates With Prognosis in Cholangiocarcinoma and Varies Based on Tumor Location. J Immunother 2021; 44:254-263. [PMID: 34191790 PMCID: PMC8373662 DOI: 10.1097/cji.0000000000000378] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/03/2021] [Indexed: 01/04/2023]
Abstract
Cholangiocarcinoma (CC) is an uncommon malignancy with increasing incidence and dismal prognosis. We conducted a comprehensive analysis of the CC tumor immune microenvironment (TIME) based on tumor location to identify therapeutic targets. We hypothesized that the TIME of CC would vary by primary tumor location and that high tumor infiltration by CD8+ T cells and low infiltration by M2 macrophages would be associated with improved survival. A retrospective analysis was conducted of 99 CC tumor samples surgically resected between 2000 and 2014. Tissue microarrays were constructed from each tumor and stained by immunohistochemistry for 24 markers of immune cells, immune activation or inhibition, programmed cell death-ligand 1, and mesothelin. Most tumors were amply infiltrated with by CD4+, CD8+, and FoxP3+ T cells, as well as by myeloid cells. Mesothelin expression ≥1+ by immunohistochemistry was found in 68% of tumors. We identified higher densities of M1 macrophages in primary distal extrahepatic CC, as well as metastatic lesions. Mesothelin expression was also significantly higher in distal extrahepatic CC. There was no association with survival of infiltration by CD4+, CD8+, or FoxP3+ T cells, mesothelin expression, or programmed cell death-ligand 1 percentage expression, however, high CD14+ myeloid cells and high CD163+ M2 macrophages were associated with worse survival. In conclusion, the CC TIME is a heterogenous milieu highly infiltrated by innate and adaptive immune cells, which differs based on primary tumor location and between primary tumors and metastatic lesions. The correlation of intratumoral M2 macrophages and myeloid cells with a worse prognosis may suggest promising immunotherapeutic targets in CC.
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Affiliation(s)
- Paul R. Kunk
- Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, Charlottesville, VA, United States
| | - Sean C. Dougherty
- Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, Charlottesville, VA, United States
| | - Kevin Lynch
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States
| | - Rachel Whitehair
- Department of Pathology, Division of Anatomic Pathology, University of Virginia Health System, Charlottesville, VA, United States
| | - Max Meneveau
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States
| | - Joseph M. Obeid
- Department of Surgery, Stony Brook University Hospital, Stony Brook, NY, United States
| | - Kevin Winters
- Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, Charlottesville, VA, United States
| | - Jennifer Y. Ju
- Department of Pathology, Division of Anatomic Pathology, University of Virginia Health System, Charlottesville, VA, United States
| | - Edward B. Stelow
- Department of Pathology, Division of Anatomic Pathology, University of Virginia Health System, Charlottesville, VA, United States
| | - Todd W. Bauer
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States
| | - Craig L. Slingluff
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States
| | - Osama E. Rahma
- Departement of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
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18
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Lü JM, Liang Z, Liu D, Zhan B, Yao Q, Chen C. Two Antibody-Guided Lactic-co-Glycolic Acid-Polyethylenimine (LGA-PEI) Nanoparticle Delivery Systems for Therapeutic Nucleic Acids. Pharmaceuticals (Basel) 2021; 14:841. [PMID: 34577541 PMCID: PMC8470087 DOI: 10.3390/ph14090841] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/14/2021] [Accepted: 08/23/2021] [Indexed: 01/10/2023] Open
Abstract
We previously reported a new polymer, lactic-co-glycolic acid-polyethylenimine (LGA-PEI), as an improved nanoparticle (NP) delivery for therapeutic nucleic acids (TNAs). Here, we further developed two antibody (Ab)-conjugated LGA-PEI NP technologies for active-targeting delivery of TNAs. LGA-PEI was covalently conjugated with a single-chain variable fragment antibody (scFv) against mesothelin (MSLN), a biomarker for pancreatic cancer (PC), or a special Ab fragment crystallizable region-binding peptide (FcBP), which binds to any full Ab (IgG). TNAs used in the current study included tumor suppressor microRNA mimics (miR-198 and miR-520h) and non-coding RNA X-inactive specific transcript (XIST) fragments; green fluorescence protein gene (GFP plasmid DNA) was also used as an example of plasmid DNA. MSLN scFv-LGA-PEI NPs with TNAs significantly improved their binding and internalization in PC cells with high expression of MSLN in vitro and in vivo. Anti-epidermal growth factor receptor (EGFR) monoclonal Ab (Cetuximab) binding to FcBP-LGA-PEI showed active-targeting delivery of TNAs to EGFR-expressing PC cells.
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Affiliation(s)
- Jian-Ming Lü
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
| | - Zhengdong Liang
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
| | - Dongliang Liu
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
| | - Bin Zhan
- National School of Tropical Medicine and Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA;
| | - Qizhi Yao
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
| | - Changyi Chen
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
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19
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Weidemann S, Perez D, Izbicki JR, Neipp M, Mofid H, Daniels T, Nahrstedt U, Jacobsen F, Bernreuther C, Simon R, Steurer S, Burandt E, Marx AH, Krech T, Clauditz TS, Jansen K. Mesothelin is Commonly Expressed in Pancreatic Adenocarcinoma but Unrelated to Cancer Aggressiveness. Cancer Invest 2021; 39:711-720. [PMID: 34143695 DOI: 10.1080/07357907.2021.1943747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Data on Mesothelin (MSLN) expression in human normal and cancerous tissues is controversial. We employed immunohistochemistry (IHC) on a tissue microarray (TMA) from 599 pancreatic cancers and 12 large tissue sections of pancreatitis. MSLN expression was highest in pancreatic adenocarcinomas (89%) and adenocarcinomas of the ampulla Vateri (79%), infrequent in pancreatitis and absent in 6 acinus cell carcinomas and normal pancreas. MSLN expression was unrelated to pathological tumor stage, grade, metastasis, and tumor-infiltrating CD8+ lymphocytes. In conclusion, pancreatic cancer may be ideally suited for putative anti- MSLN therapies, and MSLN may represent a suitable biomarker for pancreatic cancer diagnosis, especially on small biopsies.
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Affiliation(s)
- Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel Perez
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Neipp
- General, Vascular and Visceral Surgery Clinic, Itzehoe Medical Center, Itzehoe, Germany
| | - Hamid Mofid
- General, Visceral Thoracic and Vascular Surgery Clinic, Regio Clinic Pinneberg, Pinneberg, Germany
| | - Thies Daniels
- General, Visceral and Tumor Surgery Clinic, Albertinen Hospital, Hamburg, Germany
| | - Ulf Nahrstedt
- Department of General and Abdominal Surgery, Schoen Clinic Hamburg Eilbek, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kristina Jansen
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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20
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Cui W, Popat S. Pleural mesothelioma (PM) - The status of systemic therapy. Cancer Treat Rev 2021; 100:102265. [PMID: 34399145 DOI: 10.1016/j.ctrv.2021.102265] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/28/2021] [Accepted: 07/31/2021] [Indexed: 10/20/2022]
Abstract
Pleural mesothelioma (PM) remains a malignancy with poor prognosis. Despite initial disappointing response rates to single-agent chemotherapy, upfront platinum and anti-folate-based combination chemotherapy has remained the backbone of treatment for PM for the last three decades. The role of maintenance chemotherapy remains unclear; switch-maintenance gemcitabine has shown improvements in progression-free but not overall survival. The addition of antiangiogenic agents to chemotherapy yielded modest improvements in survival, both upfront in combination with platinum-pemetrexed, and in the relapsed setting. Immunotherapy, particularly PD-(L)1 inhibitors, has shown important but variable effectiveness in relapsed PM when used as monotherapy, and is an important salvage treatment after first-line chemotherapy. Furthermore, the randomized phase 3 trial of ipilimumab-nivolumab versus platinum-pemetrexed chemotherapy demonstrated improved overall survival favouring ipilimumab-nivolumab (HR 0.74, 96.6% CI 0.60-0.91; p = 0.0020), establishing this regimen as the new standard first-line treatment for PM, particularly in those with non-epithelioid histology. Increased interest in PM genomics has led to development of novel personalized therapeutics, such as those targeting DNA repair and EZH2 pathways, however with variable outcomes in trials. Targeting the membrane glycoprotein mesothelin and arginine deprivation are other important strategies under ongoing investigation. The field of PM is changing and new treatments bring hope to a largely lethal and poor prognostic malignancy. Despite these developments, current challenges include understanding the role of combination and multimodality treatments, drivers of resistance to treatment, and establishing predictive biomarkers to improve patient selection and treatment sequencing.
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Affiliation(s)
- Wanyuan Cui
- Lung Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Sanjay Popat
- Lung Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom; Thoracic Oncology, Institute of Cancer Research, London, United Kingdom.
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21
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Yeo D, Castelletti L, van Zandwijk N, Rasko JEJ. Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma. Cancers (Basel) 2021; 13:3932. [PMID: 34439085 PMCID: PMC8391149 DOI: 10.3390/cancers13163932] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/16/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody-drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.
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Affiliation(s)
- Dannel Yeo
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
| | - Laura Castelletti
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
| | - Nico van Zandwijk
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
- Concord Repatriation General Hospital, Sydney Local Health District (SLHD), Concord, NSW 2139, Australia
| | - John E. J. Rasko
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
- Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia
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22
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Yoon DH, Ibrahim A, Tatishchev S, Duldulao MPN, Lee SW, Shin J. Prevalence of mesothelin expression in peritoneal disease from colorectal and appendiceal cancers. J Surg Oncol 2021; 124:1091-1097. [PMID: 34310720 DOI: 10.1002/jso.26610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/01/2021] [Accepted: 06/19/2021] [Indexed: 11/11/2022]
Abstract
BACKGROUND Mesothelin is a cell surface glycoprotein overexpressed in 28%-58% of colorectal cancer (CRC). We hypothesized that CRC mesothelin expression contributes to peritoneal spread and that it is selectively overexpressed in those with peritoneal metastasis versus distant metastasis. METHODS This case-controlled study involved mesothelin immunohistochemistry staining of tumor specimens from patients with metastatic CRC/appendiceal cancers between 2017 and 2019. Staining reactivity was graded from trace to 4+ (low ≤1+; high >1+). Staining patterns were characterized on global (focal/patchy/diffuse) and cellular (apical/cytoplasmic) levels. Immunostaining of normal mesothelial cells served as internal control. RESULTS Thirty-one patients were identified: 11 peritoneal (study) and 20 distant metastasis (control). The control group did not include appendiceal cancers. The study group had greater proportion of high staining reactivity (55% vs. 5%; odds ratio [OR] = 20.4, 95% confidence interval [CI] 1.96-211.8). The study group had more diffuse (36% vs. 0%; OR = 22.2, 95% CI 1.1-465.3) and cytoplasmic staining patterns (73% vs. 28%; OR = 6.9, 95% CI 1.3-37.2). CONCLUSION Mesothelin expression is higher in CRC/appendiceal cancers with peritoneal metastasis than those with distant metastasis. Immunohistochemistry staining patterns suggestive of propensity towards peritoneal metastasis include diffuse and cytoplasmic staining. Mesothelin may be a potential target for novel treatments of CRC/appendiceal carcinoma with peritoneal involvement.
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Affiliation(s)
- Dong H Yoon
- Division of Colorectal Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Ahmad Ibrahim
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Sergei Tatishchev
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Marjun P N Duldulao
- Division of Colorectal Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Sang W Lee
- Division of Colorectal Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Joongho Shin
- Division of Colorectal Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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23
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Davis AP, Kao SC, Clarke SJ, Boyer M, Pavlakis N. Emerging biological therapies for the treatment of malignant pleural mesothelioma. Expert Opin Emerg Drugs 2021; 26:179-192. [PMID: 33945357 DOI: 10.1080/14728214.2021.1924670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Malignant pleural mesothelioma (MPM) has limited treatment options with minimal new therapy approvals for unresectable disease in the past 15 years. However, considerable work has occurred to develop immunotherapies and biomarker driven therapy to improve patient outcomes over this period.Areas covered: This review examines current standard of care systemic therapy in the first- and second line setting. The last 12 months has seen 2 significant trials (Checkmate 743 and CONFIRM) which provide evidence supporting the role of immunotherapy in the management of MPM. Further trials are underway to assess the role of combination chemoimmunotherapy and personalized therapy. Additionally, a large number of clinical trials are ongoing to assess the efficacy of oncoviral, dendritic cell, anti-mesothelin and chimeric antigen receptor T cell therapy in the treatment of MPM.Expert opinion: Recent Phase III trial results have established a role for immunotherapy in the management of MPM. The optimal sequencing and combination of chemotherapy and immunotherapy remains to be determined. Novel therapies for MPM are promising however efficacy remains to be determined and issues remain regarding access to and delivery of these therapies.
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Affiliation(s)
- Alexander P Davis
- Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia
| | - Steven C Kao
- Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia.,Asbestos Disease Research Institute, Rhodes, Australia.,Sydney Medical School, The University of Sydney, Sydney, Australia
| | - Stephen J Clarke
- Sydney Medical School, The University of Sydney, Sydney, Australia.,Department of Medical Oncology, Royal North Shore Hospital, St Leonards, Australia.,Genesis Care, St Leonards, Australia
| | - Michael Boyer
- Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia.,Sydney Medical School, The University of Sydney, Sydney, Australia
| | - Nick Pavlakis
- Sydney Medical School, The University of Sydney, Sydney, Australia.,Department of Medical Oncology, Royal North Shore Hospital, St Leonards, Australia.,Genesis Care, St Leonards, Australia
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24
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Mesothelin Expression in Human Tumors: A Tissue Microarray Study on 12,679 Tumors. Biomedicines 2021; 9:biomedicines9040397. [PMID: 33917081 PMCID: PMC8067734 DOI: 10.3390/biomedicines9040397] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/30/2021] [Accepted: 04/04/2021] [Indexed: 12/13/2022] Open
Abstract
Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor types showed at least occasional weak staining, including 50 (41%) tumor types with at least one strongly positive sample. Highest prevalence of MSLN positivity had ovarian carcinomas (serous 97%, clear cell 83%, endometrioid 77%, mucinous 71%, carcinosarcoma 65%), pancreatic adenocarcinoma (ductal 75%, ampullary 81%), endometrial carcinomas (clear cell 71%, serous 57%, carcinosarcoma 50%, endometrioid 45%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). MSLN was rare in cancers of the breast (7% of 1138), kidney (7% of 807), thyroid gland (1% of 638), soft tissues (0.3% of 931), and prostate (0 of 481). High expression was linked to advanced pathological tumor (pT) stage (p < 0.0001) and metastasis (p < 0.0001) in 1619 colorectal adenocarcinomas, but unrelated to parameters of malignancy in 1072 breast-, 386 ovarian-, 174 lung-, 757 kidney-, 171 endometrial-, 373 gastric-, and 925 bladder carcinomas. In summary, numerous important cancer types with high-level MSLN expression might benefit from future anti-MSLN therapies, but MSLN’s prognostic relevance appears to be limited.
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25
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A Novel 89Zr-labeled DDS Device Utilizing Human IgG Variant (scFv): "Lactosome" Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy. Life (Basel) 2021; 11:life11020158. [PMID: 33670777 PMCID: PMC7923095 DOI: 10.3390/life11020158] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 12/22/2022] Open
Abstract
“Theranostics,” a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, “Lactosome” nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the “89Zr-labeled CPP and TPP-loaded Lactosome particles” and future directions based on important milestones and recent developments in this platform.
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26
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Askan G, Basturk O. Expression of Calretinin, Marker of Mesothelial Differentiation, in Pancreatic Ductal Adenocarcinoma: A Potential Diagnostic Pitfall. Turk Patoloji Derg 2021; 37:115-120. [PMID: 33432559 PMCID: PMC10512685 DOI: 10.5146/tjpath.2020.01519] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/16/2020] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma is one of the most common causes of "peritoneal carcinomatosis" and has an insidious growth pattern. Thus, it falls into the differential diagnosis of other peritoneal malignancies including malignant mesothelioma. Recently, we have encountered an undifferentiated pancreatic carcinoma presenting with peritoneal disease and exhibiting immunoreactivity to calretinin, mimicking mesothelioma. In this study, we explored the incidence of calretinin expression in pancreatic ductal adenocarcinoma. MATERIALS AND METHODS Calretinin immunohistochemical staining was performed on the tissue microarrays (TMAs), which were created using three 0.6 mm diameter punches per tumor (n=113). Distribution and intensity of expression were evaluated. RESULTS The TMAs contained 86 well/moderately differentiated and 27 poorly differentiated/undifferentiated carcinomas. Calretinin was positive in nine tumors (8%); six with diffuse and strong staining, three with focal and/or weak staining. The incidence of calretinin expression was 15% in poorly differentiated/undifferentiated carcinomas (vs. 6% in well/moderately differentiated carcinomas, p=0.03). CONCLUSIONS Pancreatic ductal adenocarcinomas, especially when poorly differentiated/undifferentiated, may be diffusely and strongly positive for calretinin creating a potential diagnostic challenge with malignant mesothelioma. Therefore, caution should be exercised when using this marker to explore a diagnosis of malignant mesothelioma. Tumors expressing calretinin without other mesothelial markers should prompt a careful evaluation of the morphologic and immunohistochemical features to exclude other malignancies. If the diagnosis of pancreatic ductal adenocarcinoma is considered, ductal differentiation can be demonstrated by using additional immunohistochemical markers such as mucin-related glycoproteins (MUC1, MUC5AC) and/or oncoproteins (CEA, B72.3, CA125).
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Affiliation(s)
- Gokce Askan
- Department of Pathology, Rize University Training and Research Hospital, Rize, Turkey
| | - Olca Basturk
- Memorial Sloan Kettering Cancer Center, New York, USA
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27
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Rekhi B, Karmarkar S, Deodhar K, Menon S. Histopathological and immunohistochemical features of 14 peritoneal mesotheliomas with clinical outcomes and recent updates. J Cancer Res Ther 2021; 18:1683-1691. [PMID: 36412430 DOI: 10.4103/jcrt.jcrt_1292_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Malignant peritoneal mesotheliomas (MPMs) are rare tumors with overlapping clinical and histopathological features, especially with epithelial ovarian carcinomas (EOCs). There is no substantial documentation on these rare tumors from our country. Objective To study the clinicopathological features including immunohistochemical (IHC) profile and clinical outcomes of 14 MPMs, diagnosed at our institution. Materials and Methods This was a retrospective study, wherein 14 cases of MPM, occurring in female patients, diagnosed at our institution, between January 2008 and May 2019 were included, after a critical review. Results Median age was 54.5 years. Most patients presented with ascites, omental nodularity, and fat stranding. Microscopically, most cases (11, 78.6%) displayed epithelioid morphology, followed by biphasic pattern (2, 14.3%) and a single case of well-differentiated MPM. IHC, diagnostic sensitivity and specificity of calretinin were 100% (13/13) and 85.7%; of HBME1 were 100% (5/5) and 100%; and of podoplanin (D2-40) were 60% (2/5) and 100%. Other positively expressed immunomarkers were epithelial membrane antigen (n = 2/5, 40%), cytokeratin 5/6 (n = 4/4, 100%), and WT1 (n = 9/10, 90%). Most patients (5/12, 41.7%) were treated with chemotherapy. The 3-year disease-free and overall survival rates were 25.7% and 54%, respectively, including improved survival trend in patients with epithelioid type of MPMs. Conclusion MPMs are diagnosed with a combination of clinicopathological features and optimal IHC markers. Their differentiation from EOCs and other metastatic carcinomas is imperative in view of significant treatment implications.
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28
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Molloy ME, Austin RJ, Lemon BD, Aaron WH, Ganti V, Jones A, Jones SD, Strobel KL, Patnaik P, Sexton K, Tatalick L, Yu TZ, Baeuerle PA, Law CL, Wesche H. Preclinical Characterization of HPN536, a Trispecific, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors. Clin Cancer Res 2020; 27:1452-1462. [PMID: 33262134 DOI: 10.1158/1078-0432.ccr-20-3392] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/12/2020] [Accepted: 11/25/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers. EXPERIMENTAL DESIGN We designed HPN536, a 53-kDa, trispecific, T-cell-activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ε on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP). RESULTS HPN536 binds to MSLN-expressing tumor cells and to CD3ε on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans. CONCLUSIONS HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).
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Affiliation(s)
| | | | - Bryan D Lemon
- Harpoon Therapeutics, South San Francisco, California
| | - Wade H Aaron
- Harpoon Therapeutics, South San Francisco, California
| | | | - Adrie Jones
- Harpoon Therapeutics, South San Francisco, California
| | - Susan D Jones
- Harpoon Therapeutics, South San Francisco, California
| | | | | | | | | | - Timothy Z Yu
- Harpoon Therapeutics, South San Francisco, California
| | - Patrick A Baeuerle
- Harpoon Therapeutics, South San Francisco, California.,MPM Capital, Cambridge, Massachusetts.,Institute for Immunology, Ludwig-Maximilians University Munich, Planegg- Martinsried, Munich, Germany
| | - Che-Leung Law
- Harpoon Therapeutics, South San Francisco, California
| | - Holger Wesche
- Harpoon Therapeutics, South San Francisco, California
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29
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Klampatsa A, Dimou V, Albelda SM. Mesothelin-targeted CAR-T cell therapy for solid tumors. Expert Opin Biol Ther 2020; 21:473-486. [PMID: 33176519 DOI: 10.1080/14712598.2021.1843628] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Mesothelin (MSLN) is a tumor differentiation antigen normally restricted to the body's mesothelial surfaces, but significantly overexpressed in a broad range of solid tumors. For this reason, MSLN has emerged as an important target for the development of novel immunotherapies. This review focuses on anti-MSLN chimeric antigen receptor (CAR) T cell immunotherapy approaches.Areas covered: A brief overview of MSLN as a therapeutic target and existing anti-MSLN antibody-based drugs and vaccines is provided. A detailed account of anti-MSLN CAR-T cell approaches utilized in preclinical models is presented. Finally, a comprehensive summary of currently ongoing and completed anti-MSLN CAR-T cell clinical trials is discussed.Expert opinion: Initial trials using anti-MSLN CAR-T cells have been safe, but efficacy has been limited. Employing regional routes of delivery, introducing novel modifications leading to enhanced tumor infiltration and persistence, and improved safety profiles and combining anti-MSLN CAR-T cells with standard therapies, could render them more efficacious in the treatment of solid malignancies.
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Affiliation(s)
- Astero Klampatsa
- Thoracic Oncology Immunotherapy Group, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
| | - Vivian Dimou
- Thoracic Oncology Immunotherapy Group, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
| | - Steven M Albelda
- Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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30
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Duong BTV, Wu L, Green BJ, Bavaghar-Zaeimi F, Wang Z, Labib M, Zhou Y, Cantu FJP, Jeganathan T, Popescu S, Pantea J, de Perrot M, Kelley SO. A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma. EBioMedicine 2020; 61:103031. [PMID: 33045471 PMCID: PMC7553233 DOI: 10.1016/j.ebiom.2020.103031] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Malignant pleural mesothelioma (MPM) is an aggressive cancer related to asbestos exposure. Early diagnosis is challenging due to generic symptoms and a lack of biomarkers. We previously demonstrated that mesothelial precursor cells (MPC) characterized by mesothelin (MSLN)+CD90+CD34+ could be implicated in the development of mesothelioma after asbestos exposure. Here, we aimed to determine the clinical significance of detecting MPC in blood for early-stage diagnosis and prognosis of mesothelioma. METHODS Due to the rarity of MPC in blood, it is challenging to identify this cell population using conventional techniques. Hence, we have developed a microfluidic liquid biopsy platform called MesoFind that utilizes an immunomagnetic, mesothelin capture strategy coupled with immunofluorescence to identify rare populations of cells at high sensitivity and precision. To validate our technique, we compared this approach to flow cytometry for the detection of MPC in murine blood and lavage samples. Upon successful validation of the murine samples, we then proceeded to examine circulating MPC in 23 patients with MPM, 23 asbestos-exposed individuals (ASB), and 10 healthy donors (HD) to evaluate their prognostic and diagnostic value. FINDING MPC were successfully detected in the blood of murine samples using MesoFind but were undetectable with flow cytometry. Circulating MPC were significantly higher in patients with epithelioid MPM compared to HD and ASB. The MPC subpopulation, MSLN+ and CD90+, were upregulated in ASB compared to HD suggesting an early role in pleural damage from asbestos. The MPC subpopulation, MSLN+ and CD34+, in contrast, were detected in advanced MPM and associated with markers of poor prognosis, suggesting a predominant role during cancer progression. INTERPRETATION The identification of circulating MPC presents an attractive solution for screening and early diagnosis of epithelioid mesothelioma. The presence of different subtypes of MPC have a prognostic value that could be of assistance with clinical decisions in patients with MPM. FUNDING Princess Margaret Hospital Foundation Mesothelioma Research Fund, Toronto General & Western Hospital Foundation.
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Affiliation(s)
- Bill T V Duong
- Department of Chemistry, University of Toronto, 80 St George St., Toronto, Ontario M5S 3H6, Canada
| | - Licun Wu
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, 101 College St., Toronto, Ontario M5G 1L7, Canada
| | - Brenda J Green
- Institute for Biomaterials and Biomedical Engineering, University of Toronto, 164 College St., Toronto, Ontario M5S 3G9, Canada
| | - Fatemeh Bavaghar-Zaeimi
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, 101 College St., Toronto, Ontario M5G 1L7, Canada; Division of Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Centre, University Health Network, 200 Elizabeth St., Toronto, Ontario M5G 2C4, Canada
| | - Zongjie Wang
- Institute for Biomaterials and Biomedical Engineering, University of Toronto, 164 College St., Toronto, Ontario M5S 3G9, Canada; The Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Rd., Toronto, Ontario M5S 3G4, Canada
| | - Mahmoud Labib
- Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Yuxiao Zhou
- Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Fernando J P Cantu
- Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Thurgaa Jeganathan
- Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Sandra Popescu
- Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Jennifer Pantea
- Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Marc de Perrot
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, 101 College St., Toronto, Ontario M5G 1L7, Canada; Division of Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Centre, University Health Network, 200 Elizabeth St., Toronto, Ontario M5G 2C4, Canada; Department of Immunology, University of Toronto, 27 King's College Circle, Toronto, Ontario M5S 1A1, Canada.
| | - Shana O Kelley
- Department of Chemistry, University of Toronto, 80 St George St., Toronto, Ontario M5S 3H6, Canada; Institute for Biomaterials and Biomedical Engineering, University of Toronto, 164 College St., Toronto, Ontario M5S 3G9, Canada; Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada; Department of Biochemistry, University of Toronto, 27 King's College Circle, Toronto, Ontario M5S 1A1, Canada.
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31
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Su Y, Zhang X, Bidlingmaier S, Behrens CR, Lee NK, Liu B. ALPPL2 Is a Highly Specific and Targetable Tumor Cell Surface Antigen. Cancer Res 2020; 80:4552-4564. [PMID: 32868383 PMCID: PMC7572689 DOI: 10.1158/0008-5472.can-20-1418] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/29/2020] [Accepted: 08/19/2020] [Indexed: 11/16/2022]
Abstract
Identification of tumor-specific cell surface antigens has proven challenging, as the vast majority of tumor-associated antigens are also expressed in normal tissues. In mesothelioma, we identified a highly specific tumor cell surface antigen that can be targeted for therapy development. Mesothelioma is caused by malignant transformation of the mesothelium, is incurable, and can be categorized into three histologic subtypes: epithelioid, biphasic, and sarcomatoid. To identity novel mesothelioma cell surface antigens with broad subtype coverage and high tissue specificity, we have previously selected phage antibody display libraries on live mesothelioma cells and tissues following counterselection on normal cells and identified a panel of human antibodies that bind all subtypes of mesothelioma, but not normal mesothelium. One of the antibodies, M25, showed high specificity against an antigen we identify here as ALPPL2. IHC on normal human tissues found that ALPPL2 is expressed only on placental trophoblasts, but not on any other normal tissues. This significant tissue specificity and broad tumor type coverage suggest that ALPPL2 could be an excellent cell surface target for therapeutic development against mesothelioma. To evaluate therapeutic potential of ALPPL2 targeting, an ALPPL2-targeted antibody-drug conjugate was developed and demonstrated potent and specific tumor killing in vitro and in vivo against both epithelioid and sarcomatoid mesothelioma. Thus, ALPPL2 belongs to a rare class of cell surface antigens classified as truly tumor specific and is well suited for therapy development against ALPPL2-expressing tumors. SIGNIFICANCE: These findings identify ALPP2 as a true tumor-specific cell surface antigen whose tissue specificity enables the development of novel therapies.
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Affiliation(s)
- Yang Su
- Department of Anesthesia, University of California, San Francisco, San Francisco, California
| | - Xin Zhang
- Department of Anesthesia, University of California, San Francisco, San Francisco, California
| | - Scott Bidlingmaier
- Department of Anesthesia, University of California, San Francisco, San Francisco, California
| | - Christopher R Behrens
- Department of Anesthesia, University of California, San Francisco, San Francisco, California
| | - Nam-Kyung Lee
- Department of Anesthesia, University of California, San Francisco, San Francisco, California
| | - Bin Liu
- Department of Anesthesia, University of California, San Francisco, San Francisco, California.
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
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Suzuki T, Yamagishi Y, Einama T, Koiwai T, Yamasaki T, Fukumura-Koga M, Ishibashi Y, Takihata Y, Shiraishi T, Miyata Y, Iwasaki T, Shinto E, Sato K, Ueno H, Yamamoto J, Kishi Y, Tsuda H. Membrane mesothelin expression positivity is associated with poor clinical outcome of luminal-type breast cancer. Oncol Lett 2020; 20:193. [PMID: 32952662 PMCID: PMC7479516 DOI: 10.3892/ol.2020.12055] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 08/04/2020] [Indexed: 12/28/2022] Open
Abstract
Mesothelin is expressed in various types of malignant tumors. The present study immunohistochemically investigated mesothelin expression and its clinicopathological significance in each subtype of breast cancer, with special reference to its cellular localization, in particular, membrane mesothelin expression. Using tissue specimens from 482 patients with breast cancer, immunohistochemistry was used to study mesothelin expression and help classify its localization as membrane or cytoplasmic expression. Mesothelin expression was detected in 77 (16.0%) cases and was the highest in triple-negative breast cancer (31/75; 41.3%), followed by human epithelial growth factor receptor type 2 type (6/33, 18.2%) and luminal type (36/374; 9.6%). Among the 482 cases, membrane mesothelin expression was detected in 73 cases and was significantly associated with a negative hormone receptor status, higher Ki-67 labeling index, nuclear grade 3 and a lower relapse-free survival rate. Cytoplasmic mesothelin expression was not significantly associated with a lower relapse-free survival rate (P=0.058). In the 343 cases of luminal type, the membrane mesothelin expression-positive group had significantly worse prognosis than the membrane mesothelin-expression-negative group (P=0.042). There was no significant difference in the relapse-free survival rate according to the membrane mesothelin expression status in the triple-negative type and other types. It was suggested that membrane mesothelin expression in luminal type breast cancer is associated with a lower rate of relapse-free survival.
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Affiliation(s)
- Takafumi Suzuki
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Yoji Yamagishi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.,Department of Basic Pathology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Tomomi Koiwai
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Tamio Yamasaki
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Makiko Fukumura-Koga
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Yusuke Ishibashi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Yasuhiro Takihata
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Takehiro Shiraishi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Yoichi Miyata
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Toshimitsu Iwasaki
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Eiji Shinto
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Kimiya Sato
- Department of Basic Pathology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Junji Yamamoto
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Hitoshi Tsuda
- Department of Basic Pathology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
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Hassan R, Alewine C, Mian I, Spreafico A, Siu LL, Gomez‐Roca C, Delord J, Italiano A, Lassen U, Soria J, Bahleda R, Thomas A, Steinberg SM, Peer CJ, Figg WD, Niederfellner G, Méresse Naegelen V, Pastan I. Phase 1 study of the immunotoxin LMB‐100 in patients with mesothelioma and other solid tumors expressing mesothelin. Cancer 2020; 126:4936-4947. [DOI: 10.1002/cncr.33145] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 11/07/2022]
Affiliation(s)
- Raffit Hassan
- Thoracic and GI Malignancies Branch Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
| | - Christine Alewine
- Laboratory of Molecular Biology Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
| | - Idrees Mian
- Thoracic and GI Malignancies Branch Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
| | - Anna Spreafico
- Division of Medical Oncology and Hematology Princess Margaret Cancer Centre University Health NetworkUniversity of Toronto Toronto Ontario Canada
| | - Lillian L. Siu
- Division of Medical Oncology and Hematology Princess Margaret Cancer Centre University Health NetworkUniversity of Toronto Toronto Ontario Canada
| | | | | | - Antoine Italiano
- Department of Medicine Bergonie Institute Bordeaux France
- Faculty of Medicine University of Bordeaux Bordeaux France
| | - Ulrik Lassen
- Department of Oncology Rigshospitalet Copenhagen Denmark
- Department of Clinical Medicine University of Copenhagen Copenhagen Denmark
| | - Jean‐Charles Soria
- Gustave Roussy Institute Villejuif France
- University of Paris–South Orsay France
| | | | - Anish Thomas
- Developmental Therapeutics Branch Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
| | - Seth M. Steinberg
- Biostatistics and Data Management Section Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
| | - Cody J. Peer
- Clinical Pharmacology Program Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
| | - William D. Figg
- Clinical Pharmacology Program Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
- Genitourinary Malignancies Branch Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
| | | | | | - Ira Pastan
- Laboratory of Molecular Biology Center for Cancer Research National Cancer InstituteNational Institutes of Health Bethesda Maryland
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Possible reversibility between epithelioid and sarcomatoid types of mesothelioma is independent of ERC/mesothelin expression. Respir Res 2020; 21:187. [PMID: 32677949 PMCID: PMC7364551 DOI: 10.1186/s12931-020-01449-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 07/08/2020] [Indexed: 12/12/2022] Open
Abstract
Background Mesothelioma is histologically divided into three subgroups: epithelioid, sarcomatoid, and biphasic types. The epithelioid or sarcomatoid type is morphologically defined by polygonal or spindle-like forms of cells, respectively. The biphasic type consists of both components. It is not yet understood how histological differentiation of mesothelioma is regulated. ERC/mesothelin is expressed in most cases of the epithelioid type, but not in the sarcomatoid type of mesothelioma. Consequently, its expression is well correlated to the histological subtype. We hypothesized that ERC/mesothelin expression influences the histological differentiation of mesothelioma, and tested this hypothesis. Methods We performed studies using the overexpression or knockdown of ERC/mesothelin in mesothelioma cells to examine its effect on cellular morphology, growth kinetics, or migration/invasion activity, in vitro. We then transplanted ERC/mesothelin-overexpressing and control cells into the intraperitoneal space of mice. We examined the effect of ERC/mesothelin overexpression on mouse survival and tumor phenotype. Results In vitro cell culture manipulations of ERC/mesothelin expression did not affect cellular morphology or proliferation, although its overexpression enhanced cellular adhesion and the migration/invasion activity of mesothelioma cells. The survival rate of mice following intraperitoneal transplantation of ERC/mesothelin-overexpressing mesothelioma cells was significantly lower than that of mice with control cells. The histological evaluation of the tumors, however, did not show any morphological difference between two groups, and our hypothesis was not validated. Unexpectedly, both groups (ERC/mesothelin-overexpressing and control) of mesothelioma cells that were morphologically monophasic and spindle-like in vitro differentiated into a biphasic type consisting of polygonal and spindle-like components in the transplanted tumor, irrespective of ERC/mesothelin expression. Conclusions These results suggested that the histological transition of mesothelioma between epithelioid and sarcomatoid types may be reversible and regulated not by ERC/mesothelin, but by other unknown mechanisms.
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Belderbos RA, Vroman H, Aerts JGJV. Cellular Immunotherapy and Locoregional Administration of CAR T-Cells in Malignant Pleural Mesothelioma. Front Oncol 2020; 10:777. [PMID: 32582537 PMCID: PMC7283907 DOI: 10.3389/fonc.2020.00777] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is a treatment recalcitrant tumor with a poor overall survival (OS). Current approved treatment consists of first line chemotherapy that only modestly increases OS, illustrating the desperate need for other treatment options in MPM. Unfortunately, clinical studies that investigate the effectivity of checkpoint inhibitor (CI) treatment failed to improve clinical outcome over current applied therapies. In general, MPM is characterized as an immunological cold tumor with low T-cell infiltration, which could explain the disappointing results of clinical trials investigating CI treatment in MPM. Currently, many other therapeutic approaches, such as cellular therapies and cancer vaccines are investigated that could induce a tumor-specific immune response and increase of the number of tumor-infiltrating lymphocytes. In this review we will discuss these novel treatment approaches for MPM.
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Affiliation(s)
- Robert A Belderbos
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, Rotterdam, Netherlands
| | - Heleen Vroman
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, Rotterdam, Netherlands
| | - Joachim G J V Aerts
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, Rotterdam, Netherlands
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Le Stang N, Burke L, Blaizot G, Gibbs AR, Lebailly P, Clin B, Girard N, Galateau-Sallé F. Differential Diagnosis of Epithelioid Malignant Mesothelioma With Lung and Breast Pleural Metastasis: A Systematic Review Compared With a Standardized Panel of Antibodies-A New Proposal That May Influence Pathologic Practice. Arch Pathol Lab Med 2020; 144:446-456. [PMID: 31389715 DOI: 10.5858/arpa.2018-0457-oa] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
CONTEXT.— Pleural mesothelioma is a rare cancer with an often-challenging diagnosis because of its potential to be a great mimicker of many other tumors. Among them, primary lung and breast cancers are the 2 main causes of pleural metastasis. The development and application of targeted therapeutic agents have made it even more important to achieve an accurate diagnosis. In this setting, international guidelines have recommended the use of 2 positive and 2 negative immunohistochemical biomarkers. OBJECTIVES.— To define the most highly specific and sensitive minimum set of antibodies for routine practice to use for the separation of epithelioid malignant mesothelioma from lung and breast metastasis and to determine the most relevant expression cutoff. DESIGN.— To provide information at different levels of expression of 16 mesothelial and epithelial biomarkers, we performed a systematic review of articles published between 1979 and 2017, and we compared those data to results from the Mesothelioma Telepathology Network (MESOPATH) of the standardized panel used in routine practice database since 1998. RESULTS.— Our results indicate that the following panel of markers-calretinin (poly)/thyroid transcription factor 1 (TTF-1; clone 8G7G3/1) and calretinin (poly)/estrogen receptor-α (ER-α; clone EP1)-should be recommended; ultimately, based on the MESOPATH database, we highlight their relevance which are the most sensitive and specific panel useful to the differential diagnosis at 10% cutoff. CONCLUSIONS.— Highlighted by their relevance in the large cohort reported, we recommend 2 useful panels to the differential diagnosis at 10% cutoff.
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Affiliation(s)
- Nolwenn Le Stang
- From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sallé), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sallé), Léon Bérard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard)
| | - Louise Burke
- From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sallé), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sallé), Léon Bérard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard)
| | - Gaetane Blaizot
- From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sallé), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sallé), Léon Bérard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard)
| | - Allen R Gibbs
- From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sallé), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sallé), Léon Bérard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard)
| | - Pierre Lebailly
- From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sallé), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sallé), Léon Bérard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard)
| | - Bénédicte Clin
- From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sallé), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sallé), Léon Bérard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard)
| | - Nicolas Girard
- From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sallé), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sallé), Léon Bérard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard)
| | - Françoise Galateau-Sallé
- From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sallé), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sallé), Léon Bérard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard)
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Hassan R, Blumenschein GR, Moore KN, Santin AD, Kindler HL, Nemunaitis JJ, Seward SM, Thomas A, Kim SK, Rajagopalan P, Walter AO, Laurent D, Childs BH, Sarapa N, Elbi C, Bendell JC. First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors. J Clin Oncol 2020; 38:1824-1835. [PMID: 32213105 PMCID: PMC7255978 DOI: 10.1200/jco.19.02085] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.
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Affiliation(s)
- Raffit Hassan
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - George R Blumenschein
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kathleen N Moore
- Stephenson Oklahoma Cancer Center at University of Oklahoma, Oklahoma City, OK/Sarah Cannon Research Institute, Nashville, TN
| | | | | | - John J Nemunaitis
- Division of Hematology and Medical Oncology, Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Shelly M Seward
- Wayne State University Karmanos Cancer Institute, Huntington Woods, MI
| | - Anish Thomas
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | | | | | | | | | | | | | - Cem Elbi
- Bayer HealthCare Pharmaceuticals, Whippany, NJ
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Evaluation of soluble mesothelin-related peptides and MSLN genetic variability in asbestos-related diseases. Radiol Oncol 2020; 54:86-95. [PMID: 32187018 PMCID: PMC7087423 DOI: 10.2478/raon-2020-0011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background Asbestos exposure is associated with increased risk of several diseases, including malignant mesothelioma (MM). Cell surface glycoprotein mesothelin is overexpressed in MM and serum soluble mesothelin-related peptides (SMRP) were already proposed as a diagnostic or prognostic biomarker in MM. However, interindividual variability in serum SMRP levels limits the clinical usefulness. Our primary objective was to investigate the influence of MSLN rs1057147 on serum SMRP levels in asbestos-exposed subjects and patients with asbestos-related diseases as well as on survival in MM. Subjects and methods Among 782 asbestos-exposed subjects and patients with asbestos-related diseases, 154 had MM. Serum SMRP levels were determined using sandwich enzyme-linked immunosorbent assay. All subjects were genotyped for MSLN rs1057147 polymorphism using competitive allele-specific polymerase chain reaction. Nonparametric tests, logistic and Cox regression were used in statistical analysis to compare different subject groups. Results MM patients had significantly higher SMRP levels than all other subjects (p < 0.001). Compared to wild-type MSLN rs1057147 genotype, both heterozygotes and carriers of two polymorphic alleles had significantly higher SMRP levels among subjects without MM (p < 0.001), but not in MM patients (p = 0.424). If genotype information was included, specificity of SMRP increased from 88.5% to 92.7% for the optimal cutoff value. Overall survival was significantly shorter in MM patients carrying at least one polymorphic rs1057147 allele (HR = 1.72, 95% CI = 1.15-2.55, p = 0.008). Conclusions MSLN genetic variability affects serum SMRP levels and was associated with shorter survival of MM patients. Combination of genetic and serum factors could therefore serve as a better diagnostic or prognostic biomarker in MM patients.
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Shiraishi T, Shinto E, Nearchou IP, Tsuda H, Kajiwara Y, Einama T, Caie PD, Kishi Y, Ueno H. Prognostic significance of mesothelin expression in colorectal cancer disclosed by area-specific four-point tissue microarrays. Virchows Arch 2020; 477:409-420. [PMID: 32107600 DOI: 10.1007/s00428-020-02775-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/17/2020] [Accepted: 02/13/2020] [Indexed: 02/06/2023]
Abstract
Mesothelin (MSLN) is a cell surface glycoprotein present in many cancer types. Its expression is generally associated with an unfavorable prognosis. This study examined the prognostic significance of MSLN expression in different areas of individual colorectal cancers (CRCs) using tissue microarrays (TMAs) by enrolling 314 patients with stage II (T3-T4, N0, M0) CRCs. Using formalin-fixed paraffin-embedded tissue blocks from patients, TMA blocks were constructed. Tissue core specimens were obtained from submucosal invasive front (Fr-sm), subserosal invasive front (Fr-ss), central area (Ce), and rolled edge (Ro) of each tumor. Using these four-point TMA sets, MSLN expression was immunohistochemically surveyed. The area-specific prognostic significance of MSLN expression was evaluated. A deep learning convolutional neural network algorithm was used for imaging analysis and evaluating our judgment's objectivity. MSLN staining ratio was positively correlated between the manual and machine-learning analyses (r = 0.71). The correlation coefficient between Ro and Ce, Ro and Fr-sm, and Ro and Fr-ss was r = 0.63, r = 0.54, and r = 0.61, respectively. Disease-specific survival curves for the MSLN-positive and MSLN-negative groups in Fr-sm, Fr-ss, and Ro were significantly different (five-year survival rates 88.1% and 95.5% (P = 0.024), 85.0 and 96.2% (P = 0.0087), 87.8 and 95.5% (P = 0.051), and 77.9 and 95.8% (P = 0.046) for Fr-sm, Fr-ss, Ce, and Ro, respectively). The analysis performed using area-specific four-point TMAs clearly demonstrated that MSLN expression in stage II CRC was relatively homogeneous within tumors. Additionally, high MSLN expression showed or tended to show unfavorable prognostic significance regardless of the tumor area.
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Affiliation(s)
- Takehiro Shiraishi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-0042, Japan
| | - Eiji Shinto
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-0042, Japan.
| | - Ines P Nearchou
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, KY16 9TF, UK
| | - Hitoshi Tsuda
- Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-0042, Japan
| | - Yoshiki Kajiwara
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-0042, Japan
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-0042, Japan
| | - Peter D Caie
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, KY16 9TF, UK
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-0042, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-0042, Japan
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Nichetti F, Marra A, Corti F, Guidi A, Raimondi A, Prinzi N, de Braud F, Pusceddu S. The Role of Mesothelin as a Diagnostic and Therapeutic Target in Pancreatic Ductal Adenocarcinoma: A Comprehensive Review. Target Oncol 2019; 13:333-351. [PMID: 29656320 DOI: 10.1007/s11523-018-0567-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesothelin is a tumor differentiation antigen, which is highly expressed in several solid neoplasms, including pancreatic cancer. Its selective expression on malignant cells and on only a limited number of healthy tissues has made it an interesting candidate for investigation as a diagnostic and prognostic biomarker and as a therapeutic target. Based on a strong preclinical rationale, a number of therapeutic agents targeting mesothelin have entered clinical trials, including immunotoxins, monoclonal antibodies, antibody-drug conjugates, cancer vaccines, and adoptive T cell therapies with chimeric antigen receptors. In pancreatic cancer, mesothelin has been investigated mainly to address two unmet issues: the urgent need for new laboratory techniques for early tumor detection and the lack of successfully targetable oncogenic alterations for patients' treatment. In this review, we describe the clinicopathological significance of mesothelin expression in pancreatic cancer initiation and progression, we summarize available studies evaluating mesothelin as a potential diagnostic and prognostic biomarker in this disease, and we discuss current evidence and future perspectives of preclinical and clinical studies testing mesothelin as a molecular target for pancreatic cancer treatment.
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Affiliation(s)
- Federico Nichetti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy.
| | - Antonio Marra
- Medical Oncology Unit, Azienda Ospedaliera San Paolo, Milan, Italy
| | - Francesca Corti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Alessandro Guidi
- Medical Oncology Unit, Azienda Ospedaliera San Gerardo, Monza, Italy
| | - Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Natalie Prinzi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Filippo de Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
- Department of Oncology, Università degli Studi di Milano, Milan, Italy
| | - Sara Pusceddu
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
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Yakushiji H, Kobayashi K, Takenaka F, Kishi Y, Shinohara M, Akehi M, Sasaki T, Ohno E, Matsuura E. Novel single-chain variant of antibody against mesothelin established by phage library. Cancer Sci 2019; 110:2722-2733. [PMID: 31461572 PMCID: PMC6726835 DOI: 10.1111/cas.14150] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/18/2019] [Accepted: 07/21/2019] [Indexed: 01/29/2023] Open
Abstract
Mesothelin (MSLN) shows increased expression in various cancer cells. For clinical application of antibodies as a positron emission tomography (PET) imaging reagent, a human shortened antibody is essential both for avoiding redundant immune responses and for providing rapid imaging. Therefore, we cloned a single‐chain fragment of variable regions (scFv) from a human‐derived gene sequence. This was achieved through the construction of a naïve phage library derived from human tonsil lymphocytes. Using a column with human recombinant MSLN, we carried out bio‐panning of phage‐variants by colony formation. We first obtained 120 clones that were subjected to selection in an ELISA using human recombinant MSLN as a solid phase antigen, and 15 phage clones of scFv with a different sequence were selected and investigated by flow cytometry (FCM). Then, six variants were selected and the individual scFv gene was synthesized in the VL and VH domains and expressed in Chinese hamster ovary cells. Mammalian cell‐derived human‐origin scFv clones were analyzed by FCM again, and one MSLN highly specific scFv clone was established. PET imaging by 89Zr‐labeled scFv was done in mice bearing xenografts with MSLN‐expressing cancer cells, and tumor legions were successfully visualized. The scFv variant established in the present study may be potentially useful for cancer diagnosis by PET imaging.
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Affiliation(s)
- Hiromasa Yakushiji
- Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.,Department of Medical Life Science Faculty of Medical Bioscience Kyushu, University of Health and Welfare, Miyazaki, Japan
| | - Kazuko Kobayashi
- Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.,Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Fumiaki Takenaka
- Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshiro Kishi
- Department of Research and Development, Ina Institute, Medical & Biological Laboratories, Co., Ltd, Ina, Japan
| | - Midori Shinohara
- Department of Research and Development, Ina Institute, Medical & Biological Laboratories, Co., Ltd, Ina, Japan
| | - Masaru Akehi
- Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Takanori Sasaki
- Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Eiji Ohno
- Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto, Japan
| | - Eiji Matsuura
- Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.,Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.,Neutron Therapy Research Center, Okayama University, Okayama, Japan
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Abstract
CAR-T cell therapy targeting CD19 has achieved remarkable success in the treatment of B cell malignancies, while various solid malignancies are still refractory for lack of suitable target. In recent years, a large number of studies have sought to find suitable targets with low “on target, off tumor” concern for the treatment of solid tumors. Mesothelin (MSLN), a tumor-associated antigen broadly overexpressed on various malignant tumor cells, while its expression is generally limited to normal mesothelial cells, is an attractive candidate for targeted therapy. Strategies targeting MSLN, including antibody-based drugs, vaccines and CAR-T therapies, have been assessed in a large number of preclinical investigations and clinical trials. In particular, the development of CAR-T therapy has shown great promise as a treatment for various types of cancers. The safety, efficacy, doses, and pharmacokinetics of relevant strategies have been evaluated in many clinical trials. This review is intended to provide a brief overview of the characteristics of mesothelin and the development of strategies targeting MSLN for solid tumors. Further, we discussed the challenges and proposed potential strategies to improve the efficacy of MSLN targeted immunotherapy.
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Affiliation(s)
- Jiang Lv
- 1Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,2Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,3University of Chinese Academy of Sciences, Shijingshan District, Beijing, China
| | - Peng Li
- 1Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,2Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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Cavallari I, Urso L, Sharova E, Pasello G, Ciminale V. Liquid Biopsy in Malignant Pleural Mesothelioma: State of the Art, Pitfalls, and Perspectives. Front Oncol 2019; 9:740. [PMID: 31475103 PMCID: PMC6705182 DOI: 10.3389/fonc.2019.00740] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 07/23/2019] [Indexed: 12/12/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to asbestos exposure. Although the risk factors for MPM are well-known, the majority of MPM patients are diagnosed at an advanced stage and have a very poor prognosis. Circulating biomarkers for early diagnosis remain to be identified, and the current standard for MPM diagnosis relies on pleural biopsies. Robust non-invasive tests for the screening of asbestos-exposed subjects are therefore an important unmet clinical need. This review provides a critical summary of recent liquid biopsy-based studies aimed at discovering novel blood-based circulating biomarkers for the early diagnosis and prognostic stratification of MPM patients.
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Affiliation(s)
- Ilaria Cavallari
- Immunologia e Diagnostica Molecolare Oncologica (IDMO), Istituto Oncologico Veneto IOV- IRCCS, Padova, Italy
| | - Loredana Urso
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
| | - Evgeniya Sharova
- Immunologia e Diagnostica Molecolare Oncologica (IDMO), Istituto Oncologico Veneto IOV- IRCCS, Padova, Italy
| | - Giulia Pasello
- Immunologia e Diagnostica Molecolare Oncologica (IDMO), Istituto Oncologico Veneto IOV- IRCCS, Padova, Italy
| | - Vincenzo Ciminale
- Immunologia e Diagnostica Molecolare Oncologica (IDMO), Istituto Oncologico Veneto IOV- IRCCS, Padova, Italy.,Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
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Mesothelium and Malignant Mesothelioma. J Dev Biol 2019; 7:jdb7020007. [PMID: 30965570 PMCID: PMC6630312 DOI: 10.3390/jdb7020007] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 04/02/2019] [Accepted: 04/05/2019] [Indexed: 02/06/2023] Open
Abstract
The mesothelium is an epithelial structure derived from the embryonic mesoderm. It plays an important role in the development of a number of different organs, including the heart, lungs, and intestines. In this publication, we discuss aspects of the development of the mesothelium, where mesothelial structures can be found, and review molecular and cellular characteristics associated with the mesothelium. Furthermore, we discuss the involvement of the mesothelium in a number of disease conditions, in particular in the pathogenesis of mesotheliomas with an emphasis on malignant pleural mesothelioma (MPM)—a primary cancer developing in the pleural cavity.
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Shiraishi T, Shinto E, Mochizuki S, Tsuda H, Kajiwara Y, Okamoto K, Einama T, Hase K, Ueno H. Mesothelin expression has prognostic value in stage ΙΙ/ΙΙΙ colorectal cancer. Virchows Arch 2019; 474:297-307. [DOI: 10.1007/s00428-018-02514-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/08/2018] [Accepted: 12/17/2018] [Indexed: 11/24/2022]
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Subbarayan D, Bhattacharya J, Rani P, Khuraijam B, Jain S. Use of Panel of Markers in Serous Effusion to Distinguish Reactive Mesothelial Cells from Adenocarcinoma. J Cytol 2019; 36:28-31. [PMID: 30745736 PMCID: PMC6343394 DOI: 10.4103/joc.joc_13_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Introduction: Although cytological examination helps in diagnosis of malignancy in serous effusion, at times it is difficult to differentiate atypical reactive mesothelial cells from adenocarcinoma (AC) cells. To resolve this problem, various ancillary methods have been used. Immunocytochemistry (ICC) is one such commonly used technique in which various panel of antibodies has been tried. Unfortunately, so far no unique marker is available to solve this issue. Hence, the present study evaluates the efficacy of four antibody panel comprising of MOC-31, epithelial membrane antigen (EMA), calretinin (CAL), and mesothelin (MES) to solve this problem. Materials and Methods: Forty-two cases suspected of malignant effusion in pleural/peritoneal fluid and 42 cases of reactive effusion were included. Cytospin smears were prepared and stained with Giemsa stain for cytomorphological diagnosis. Cytospin smears and cell blocks were made forICC. ICC for MOC-31, EMA, CAL, and MES was performed. Results: Among the suspected malignant effusion cases, 30 cases were AC and 12 cases were suspicious for malignancy by cytomorphology. MOC31 demonstrated 100% sensitivity (Sn) and 95.24% specificity (Sp), and EMA had 88.1% Sn and 92.86% Sp for AC cases. CAL demonstrated 100% and 97.62%, and MES 97.62% and 88.1% Sn and Sp in reactive mesothelial cells, respectively. Conclusion: In conclusion, combination of MOC-31 and CAL as a limited panel will be helpful in giving an appropriate diagnosis in difficult cases and thereby, help in patient management. In addition, ICC on cytospin smears gave results similar to cell blocks, and if standardised cytospin is simple technique to perform, unlike cell blocks.
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Affiliation(s)
- Devi Subbarayan
- Pathology Department, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, Tamil Nadu, India
| | - Jenna Bhattacharya
- Pathology Department, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
| | - Poonam Rani
- Pathology Department, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
| | - Bembem Khuraijam
- Pathology Department, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
| | - Shyama Jain
- Pathology Department, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
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The anti-mesothelin monoclonal antibody amatuximab enhances the anti-tumor effect of gemcitabine against mesothelin-high expressing pancreatic cancer cells in a peritoneal metastasis mouse model. Oncotarget 2018; 9:33844-33852. [PMID: 30333914 PMCID: PMC6173461 DOI: 10.18632/oncotarget.26117] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 09/01/2018] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer often has a very poor prognosis, even after complete resection. The recurrence of hepatic and peritoneal metastases is an important prognostic factor; therefore, the development of improved adjuvant therapy is urgently required. Mesothelin is a cell surface glycoprotein whose expression is restricted to a variety of cancer types, including pancreatic cancer. This expression pattern makes mesothelin an attractive target for cancer therapy, and several agents targeting mesothelin are currently in clinical trials. Here, we used the chimerized high-affinity anti-mesothelin monoclonal antibody amatuximab to investigate its effect on peritoneal metastasis. We used the AsPC-1 pancreatic cancer cell line engineered to express Gaussia luciferase (Gluc), (AsPC-1-Gluc) for in vivo experiments. Results showed that while amatuximab was not directly cytotoxic on an AsPC-1-Gluc tumor cells in a peritoneal metastasis model, it prevented the formation of tumor growth. In combination therapy with gemcitabine, amatuximab exhibited synergistic killing. Our results suggest that blockade of mesothelin by amatuximab may be a useful strategy for preventing the peritoneal dissemination of pancreatic cancer under an adjuvant setting.
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Tsukagoshi M, Wada S, Hirono S, Yoshida S, Yada E, Sasada T, Shirabe K, Kuwano H, Yamaue H. Identification of a novel HLA-A24-restricted cytotoxic T lymphocyte epitope peptide derived from mesothelin in pancreatic cancer. Oncotarget 2018; 9:31448-31458. [PMID: 30140382 PMCID: PMC6101134 DOI: 10.18632/oncotarget.25837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 07/12/2018] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer involves highly malignant tumors, and the development of new therapeutic strategies is critical. Mesothelin is overexpressed in infiltrating pancreatic cancer cells and plays an important role in the invasion and migration processes. In this study, we focused on mesothelin as a tumor-specific antigen target for a pancreatic cancer vaccine. We first investigated the mesothelin-derived epitope peptide restricted to HLA-A*2402. A total of 19 candidate peptides were synthesized, and we then determined their potential to induce peptide-specific cytotoxic T lymphocytes (CTLs). Peptide-specific CTLs were induced by five peptides derived from mesothelin, and these CTLs successfully exhibited peptide-specific IFN-γ production. After the expansion of each CTL, two CTL lines were established, which were induced by mesothelin-10-5 peptide (AFYPGYLCSL). These CTL lines exhibited peptide-specific cytotoxicity and IFN-γ production. Moreover, we were able to generate mesothelin-10-5 peptide-specific CTL clones. These CTL clones also had specific cytotoxic activity against HLA-A*2402-positive pancreatic cancer cells that endogenously expressed mesothelin. These results indicate that the mesothelin-10-5 peptide is a novel HLA-A*2402 restricted CTL epitope and that it is a promising candidate target for antigen-specific immunotherapy against pancreatic cancers.
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Affiliation(s)
- Mariko Tsukagoshi
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan.,Department of Innovative Cancer Immunotherapy, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan
| | - Satoshi Wada
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan.,Department of Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama Kanagawa 241-8515, Japan
| | - Seiko Hirono
- Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan
| | - Shintaro Yoshida
- Department of Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama Kanagawa 241-8515, Japan
| | - Erica Yada
- Department of Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama Kanagawa 241-8515, Japan
| | - Tetsuro Sasada
- Department of Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama Kanagawa 241-8515, Japan
| | - Ken Shirabe
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan.,Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan
| | - Hiroki Yamaue
- Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan
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Llop E, Guerrero PE, Duran A, Barrabés S, Massaguer A, Ferri MJ, Albiol-Quer M, de Llorens R, Peracaula R. Glycoprotein biomarkers for the detection of pancreatic ductal adenocarcinoma. World J Gastroenterol 2018; 24:2537-2554. [PMID: 29962812 PMCID: PMC6021768 DOI: 10.3748/wjg.v24.i24.2537] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 05/04/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PaC) shows a clear tendency to increase in the next years and therefore represents an important health and social challenge. Currently, there is an important need to find biomarkers for PaC early detection because the existing ones are not useful for that purpose. Recent studies have indicated that there is a large window of time for PaC early detection, which opens the possibility to find early biomarkers that could greatly improve the dismal prognosis of this tumor. The present manuscript reviews the state of the art of the existing PaC biomarkers. It focuses on the anomalous glycosylation process and its role in PaC. Glycan structures of glycoconjugates such as glycoproteins are modified in tumors and these modifications can be detected in biological fluids of the cancer patients. Several studies have found serum glycoproteins with altered glycan chains in PaC patients, but they have not shown enough specificity for PaC. To find more specific cancer glycoproteins we propose to analyze the glycan moieties of a battery of glycoproteins that have been reported to increase in PaC tissues and that can also be found in serum. The combination of these new candidate glycoproteins with their aberrant glycosylation together with the existing biomarkers could result in a panel, which would expect to give better results as a new tool for early diagnosis of PaC and to monitor the disease.
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Affiliation(s)
- Esther Llop
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Pedro E Guerrero
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Adrià Duran
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Sílvia Barrabés
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Anna Massaguer
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - María José Ferri
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
- Clinic Laboratory, University Hospital Dr Josep Trueta, Girona 17007, Spain
| | - Maite Albiol-Quer
- Department of Surgery, Hepato-biliary and Pancreatic Surgery Unit, University Hospital Dr Josep Trueta, Girona 17007, Spain
| | - Rafael de Llorens
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Rosa Peracaula
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
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50
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Jindal V, Arora E, Gupta S, Lal A, Masab M, Potdar R. Prospects of chimeric antigen receptor T cell therapy in ovarian cancer. Med Oncol 2018; 35:70. [PMID: 29651744 DOI: 10.1007/s12032-018-1131-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/08/2018] [Indexed: 01/12/2023]
Abstract
Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Immunotherapy provides a promising and novel treatment option for ovarian cancer. Recently, chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematological tumors and current research is going on in various solid tumors like ovarian cancer. CAR T cells are genetically engineered T cells with major histocompatibility complex-independent, tumor-specific, immune-mediated cytolytic actions against cancer cells. Initial studies of CAR T cell therapy have shown promising results in ovarian cancer, but there are some obstacles like impaired T cell trafficking, lack of antigenic targets, cytokine release syndrome and most important immunosuppressive tumor microenvironment. Optimization of design, improving tumor microenvironment and combinations with other therapies may help us in improving CAR T cell efficacy. In this review article, we highlight the current knowledge regarding CAR T cell therapy in ovarian cancer. We have discussed basic functioning of CAR T cells, their rationale and clinical outcome in ovarian cancer with limitations.
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Affiliation(s)
- Vishal Jindal
- Department of Internal Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, 01608, USA.
| | - Ena Arora
- Department of Internal Medicine, Government Medical College and Hospital, Chandigarh, India
| | - Sorab Gupta
- Department of Hematology and Oncology, Einstein Healthcare Network, Philadelphia, USA
| | - Amos Lal
- Department of Internal Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, 01608, USA
| | - Muhammad Masab
- Department of Internal Medicine, Einstein Healthcare Network, Philadelphia, USA
| | - Rashmika Potdar
- Department of Hematology and Oncology, Einstein Healthcare Network, Philadelphia, USA
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