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Boubaddi M, Rossi J, Marichez A, Marty M, Amintas S, Laurent C, Dabernat S. Preoperative Prognostic Factors in Resectable Pancreatic Cancer: State of the Art and Prospects. Ann Surg Oncol 2025; 32:4117-4127. [PMID: 40095311 DOI: 10.1245/s10434-025-17062-w] [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: 12/20/2024] [Accepted: 02/09/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Only 15% to 20% of patients with pancreatic ductal adenocarcinoma (PDAC) have access to surgical resection, which represents the only chance of curative treatment. Current resection classifications are almost exclusively anatomic and do not correlate sufficiently with patient survival. It is essential to develop preoperative prognostic factors to distinguish patients at high risk of early postoperative recurrence from those who will have prolonged survival after surgery. In some cases, PDACs may present biomolecular differences reflecting their aggressiveness that are not yet assessable by the current clinical-biologic assessment. This study aimed to assess the preoperative prognostic factors that are already available and the future perspectives being developed. METHOD This study reviewed the literature using the PubMed public database for preoperative prognostic factors for resectable PDAC. CONCLUSION Validated preoperative prognostic factors, whether clinical, biologic, radiologic, or histologic, are very important in anticipating the course of each patient's disease. The identification of potential new prognostic biomarkers such as genomic, transcriptomic, and proteomic analyses and the dosage of circulating tumor DNA are very serious avenues to be developed, but the extraction and analysis techniques as well as the interpretation of their results need to be standardized in prospective studies.
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Affiliation(s)
- Mehdi Boubaddi
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France.
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France.
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital, Bordeaux, France.
| | - Julia Rossi
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Arthur Marichez
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Marion Marty
- Tumor Biology and Tumor Bank Laboratory, CHU Bordeaux, Bordeaux, France
| | - Samuel Amintas
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Christophe Laurent
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France
| | - Sandrine Dabernat
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
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Goldmacher VS, Gershteyn I, Chari R, Kovtun Y. A bispecific anti-MUC16/anti-death receptor 5 antibody achieves effective and tumor-selective death receptor 5-mediated tumor regression. Sci Rep 2025; 15:9909. [PMID: 40121208 PMCID: PMC11929789 DOI: 10.1038/s41598-025-93927-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 03/10/2025] [Indexed: 03/25/2025] Open
Abstract
The bispecific antibody IMV-M was designed to selectively bind and cluster death receptor 5 (DR5) upon engaging the tumor antigen MUC16 through a novel mechanism-clustering multiple IMV-M molecules on a single MUC16 molecule. IMV-M demonstrated potent, MUC16-selective anti-tumor activity in vitro and in xenograft models without requiring secondary crosslinking, and a pilot non-human primate toxicity study detected no toxicity. Our findings suggest that antibody clustering effectively induces DR5 clustering, resulting in anti-tumor activity. Unlike anti-MUC16 antibody-drug conjugates (ADCs), which rely on cytotoxic payloads, this approach offers a safer and more effective therapeutic strategy. Notably, MUC16 is overexpressed in substantial subsets of ovarian, pancreatic, and lung cancers, with minimal expression in normal tissues, suggesting the broad applicability of this bispecific antibody.
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Affiliation(s)
- Victor S Goldmacher
- Research and Development, ImmuVia Inc, 245 First Street, Suite 1800, Cambridge, MA, 02142, USA.
| | - Iosif Gershteyn
- Research and Development, ImmuVia Inc, 245 First Street, Suite 1800, Cambridge, MA, 02142, USA
| | - Ravi Chari
- Research and Development, ImmuVia Inc, 245 First Street, Suite 1800, Cambridge, MA, 02142, USA
| | - Yelena Kovtun
- Research and Development, ImmuVia Inc, 245 First Street, Suite 1800, Cambridge, MA, 02142, USA
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3
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Wang X, Ding Y, Li S, Wang F, Yang L, Zhang H, Hong Z. Conditionally activated immunotoxins with prolonged half-life can enhance the anti-tumor activity. Int J Pharm 2025; 669:125003. [PMID: 39603436 DOI: 10.1016/j.ijpharm.2024.125003] [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: 08/04/2024] [Revised: 11/15/2024] [Accepted: 11/23/2024] [Indexed: 11/29/2024]
Abstract
Immunotoxin has become a highly promising therapy for treating cancer and has achieved good results in preclinical trials targeting various cancers. However, there are still some issues that limit the development and application of immunotoxins, such as short half-life and toxic side effects on healthy tissues. In this study, we designed a tumor-conditional immunotoxin called NbHSA-uPA-A1-PE24. Anti-HSA nanobody (NbHSA) was fused to the N-terminus of A1-PE24 (immunotoxin targeting mesothelin) via a linker cleavable by tumor-associated proteases, urokinase-type plasminogen activator (uPA). NbHSA binds to HSA (human serum albumin) in the blood circulation, which not only prolongs the half-life of immunotoxins, but also creates a certain spatial barrier between A1 and mesothelin, thereby reducing the toxicity of NbHSA-uPA-A1-PE24 to healthy tissues expressing mesothelin. Moreover, uPA cleavable element rendered the immunotoxin conditional activation specifically in tumor microenvironment. In animal experiments, the half-life of the newly designed immunotoxins was increased dramatically. Noted, NbHSA-uPA-A1-PE24 has better enrichment at tumor, and shows robust anti-tumor effects in multiple preclinical models, such as pancreatic cancer and gastric cancer models. The results indicate that this strategy has greater potential and higher safety for application in tumor treatment, providing new ideas and strategies for the development of immunotoxins for cancer patients.
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Affiliation(s)
- Xi Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Cancer Biology Center, Frontiers Science Center for New Organic Matter, College of Life Sciences, Nankai University, Tianjin 300071, PR China.
| | - Yu Ding
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Cancer Biology Center, Frontiers Science Center for New Organic Matter, College of Life Sciences, Nankai University, Tianjin 300071, PR China.
| | - Shuang Li
- National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin 300192, PR China.
| | - Fengwei Wang
- School of Medicine, Nankai University, Tianjin 300071, PR China; People's Hospital of Tianjin, Tianjin 300180, PR China.
| | - Liu Yang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Cancer Biology Center, Frontiers Science Center for New Organic Matter, College of Life Sciences, Nankai University, Tianjin 300071, PR China.
| | - Hongru Zhang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Cancer Biology Center, Frontiers Science Center for New Organic Matter, College of Life Sciences, Nankai University, Tianjin 300071, PR China; Nankai International Advanced Research Institute (SHENZHEN FUTIAN), Shenzhen 518045, PR China.
| | - Zhangyong Hong
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Cancer Biology Center, Frontiers Science Center for New Organic Matter, College of Life Sciences, Nankai University, Tianjin 300071, PR China; Nankai International Advanced Research Institute (SHENZHEN FUTIAN), Shenzhen 518045, PR China.
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Ewa T, Panchwagh N, Tai C, Avula LR, Joseph S, Rudloff MW, Malik N, Zhang X, Alewine C. Excess shed mesothelin disrupts pancreatic cancer cell clustering to impair peritoneal colonization. FASEB J 2024; 38:e70247. [PMID: 39673668 PMCID: PMC11646052 DOI: 10.1096/fj.202400446r] [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: 02/28/2024] [Revised: 10/18/2024] [Accepted: 12/04/2024] [Indexed: 12/16/2024]
Abstract
Peritoneum is the second most common site of metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). Peritoneal colonization is impaired in PDAC cells with knockout (KO) of the cancer surface antigen mesothelin (MSLN) or by introducing Y318A mutation in MSLN to prevent binding to mucin-16 (MUC-16). MSLN has a membrane-bound form but is also shed to release soluble MSLN (sMSLN). Their individual roles in peritoneal metastasis are unknown. Here, a C-terminal truncated MSLN mutant (∆591) incapable of cell membrane insertion but proficient in secretion was engineered. Expression of ∆591 MSLN failed to rescue peritoneal metastasis in MSLN KO cells and inhibited peritoneal colonization when overexpressed in WT PDAC cells. Exposing PDAC cells to conditioned medium (CM) containing excess sMSLN impaired cancer cell clustering in vitro and in peritoneal fluid in vivo, while CM containing only Y318A sMSLN did not. These data demonstrate that interaction of membrane-bound MSLN with MUC-16 promotes cell clustering that is critical for efficient peritoneal metastasis. However, peritoneal colonization by MSLN KO cells was rescued by expression of ∆591 mutant MSLN bearing Y318A mutation, suggesting that sMSLN also has a MUC-16-independent role in peritoneal spread. Alterations in inflammatory signaling pathways occurred following KO cell exposure to CM containing sMSLN, and CM from cancer cells with intact peritoneal metastasis provoked increased KO cell secretion of IL-1α. While excess sMSLN inhibits cell clustering and peritoneal colonization, sMSLN may also promote PDAC peritoneal metastasis independent of MUC-16.
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Affiliation(s)
- Theressa Ewa
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Neel Panchwagh
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
- Present address:
NYU Grossman School of MedicineNew YorkNew York10016USA
| | - Chin‐Hsien Tai
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Leela Rani Avula
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Sarah Joseph
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
- Present address:
Department of MedicineUniversity of VirginiaCharlottesvilleVirginia22903USA
| | - Michael W. Rudloff
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
- Present address:
Department of MedicineUniversity of North CarolinaChapel HillNorth Carolina27599USA
| | - Nargis Malik
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Xianyu Zhang
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Christine Alewine
- Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
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Duan H, Liu X, Zhang Y, Liu Y, Ji Y, Zhang Y, Fan Z, Liu S, Yang L, Xu T, Tian J, Li W, Lyu Z, Song F, Song F, Huang Y. Risk-stratified CA125 screening integrating CA125 trajectories, trajectory-specific progression and transvaginal ultrasound for ovarian cancer. J Ovarian Res 2024; 17:210. [PMID: 39462415 PMCID: PMC11514894 DOI: 10.1186/s13048-024-01535-9] [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: 03/11/2024] [Accepted: 10/09/2024] [Indexed: 10/29/2024] Open
Abstract
BACKGROUNDS Cancer antigen 125 (CA125) is widely used for screening ovarian cancer (OC), yet its effectiveness remains debated. Potential factors may include ineffective cut-off value for CA125 in screening, as well as a lack of consideration for CA125 trajectories and trajectory-specific progression. METHODS Based on data from multiple rounds of CA125 tests and transvaginal ultrasound (TVU) examinations conducted on 28,456 women in the PLCO Trial, time-dependent receiver-operating-characteristic curves (ROCs) and area-under-the-curves (tdAUCs) analyses were employed to identify the optimal CA125 cut-off values for OC screening. Participants were categorized into four CA125 trajectories: stable negative CA125 (CA125SN), loss of positive CA125 (CA125LP), stable positive CA125 (CA125SP), and gain of positive CA125 (CA125GP). The associations between different CA125 trajectories, trajectory-specific progression indicators, and OC risk were explored. The effectiveness of risk-stratified CA125 screening, incorporating CA125 trajectories, trajectory-specific progression, and TVU, was evaluated using hazard ratio and 95% confidence intervals [HR (95%CIs)], with adjustments for potential confounders. RESULTS After a median follow-up of 14.8 years for OC incidence and 23.8 years for OC mortality, 250 OC cases and 218 OC deaths were identified. The tdAUC for 10-year OC incidence with CA125 was 0.663, with an optimal cut-off value of 13.00 U/ml. Trajectory analyses showed that both CA125SP and CA125GP were significantly associated with increased risks of OC incidence [HRs (95%CIs): 2.00(1.47-2.73) and 3.06(2.25-4.16)] and mortality [HRs (95%CIs):1.58(1.13-2.21) and 2.60(1.87-3.62)] compared to CA125SN. Trajectory-specific progression analyses identified relative velocity as the optimal progression indicators for both CA125SP and CA125GP (tdAUCs: 0.712 and 0.767), with optimal cut-off values of 9% and 32% per year, respectively. Positive progression was associated with significantly increased risks of OC incidence [HRs (95%CI): 7.26(4.00-13.17) and 3.83(1.96-7.51) CA125GP and CA125SP] and mortality [HRs (95%CI): 8.03(4.15-15.56) and 6.04(2.78-13.14)] compared to negative progression. Optimized risk-stratified CA125 screening, which integrated CA125 trajectories, trajectory-specific progression, and TVU, reduced missed OC by 3.6% and improved accuracy compared to traditional screening methods. CONCLUSIONS Incorporating CA125 trajectories and trajectory-specific progression into screening protocols enhances the identification of the population at high-risk of OC. An optimized screening strategy, which includes these factors along with TVU, is recommended to improve the effectiveness of OC screening.
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Affiliation(s)
- Hongyuan Duan
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Xiaomin Liu
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Yu Zhang
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Ya Liu
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Yuting Ji
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Yunmeng Zhang
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Zeyu Fan
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Siwen Liu
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Lei Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Office for Cancer Prevention and Control, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Tingting Xu
- Department of International Affairs, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China
| | - Jing Tian
- Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China
| | - Weiqin Li
- Project Office, Tianjin Women and Children's Health Center, Tianjin, 300070, China
| | - Zhangyan Lyu
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Fangfang Song
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Fengju Song
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China
| | - Yubei Huang
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, Tianjin, 300060, China.
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Zhang XY, Hong LL, Ling ZQ. MUC16: clinical targets with great potential. Clin Exp Med 2024; 24:101. [PMID: 38758220 PMCID: PMC11101557 DOI: 10.1007/s10238-024-01365-5] [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: 03/02/2024] [Accepted: 04/29/2024] [Indexed: 05/18/2024]
Abstract
Mucin 16 (MUC16) is a membrane-bound mucin that is abnormally expressed or mutated in a variety of diseases, especially tumors, while being expressed in normal body epithelium. MUC16 and its extracellular components are often important cancer-related biomarkers. Abnormal expression of MUC16 promotes tumor progression through mesenchymal protein, PI3K/AKT pathway, JAK2/STAT3 pathway, ERK/FBW7/c-Myc, and other mechanisms, and plays an important role in the occurrence and development of tumors. In addition, MUC16 also helps tumor immune escape by inhibiting T cells and NK cells. Many drugs and trials targeting MUC16 have been developed, and MUC16 may be a new direction for future treatments. In this paper, the mechanism of action of MUC16 in the development of cancer, especially in the immune escape of tumor, is introduced in detail, indicating the potential of MUC16 in clinical treatment.
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Affiliation(s)
- Xin-Yu Zhang
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
- The Second Clinical Medical College of Zhejiang, Chinese Medicine University, Hangzhou, 310053, China
| | - Lian-Lian Hong
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Zhi-Qiang Ling
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, China.
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China.
- The Second Clinical Medical College of Zhejiang, Chinese Medicine University, Hangzhou, 310053, 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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Grasso L, Jiang Q, Hassan R, Nicolaides NC, Kline JB. NAV-003, a bispecific antibody targeting a unique mesothelin epitope and CD3ε with improved cytotoxicity against humoral immunosuppressed tumors. Eur J Immunol 2023; 53:e2250309. [PMID: 37146241 PMCID: PMC10524251 DOI: 10.1002/eji.202250309] [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: 12/05/2022] [Revised: 05/03/2023] [Accepted: 05/04/2023] [Indexed: 05/07/2023]
Abstract
Mesothelin (MSLN) is a cell surface protein overexpressed in a number of cancer types. Several antibody- and cellular-based MSLN targeting agents have been tested in clinical trials where their therapeutic efficacy has been moderate at best. Previous studies using antibody and Chimeric Antigen Receptor-T cells (CAR-T) strategies have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found that certain MSLN-positive tumors can produce proteins that can bind to subsets of IgG1-type antibodies and suppress their immune effector activities. In an attempt to develop an improved anti-MSLN targeting agent, we engineered a humanized divalent anti-MSLN/anti-CD3ε bispecific antibody that avoids suppressive factors, can target a MSLN epitope proximal to the tumor cell surface, and is capable of effectively binding, activating, and redirecting T cells to the surface of MSLN-positive tumor cells. NAV-003 has shown significantly improved tumor cell killing against lines producing immunosuppressive proteins in vitro and in vivo. Moreover, NAV-003 demonstrated good tolerability in mice and efficacy against patient-derived mesothelioma xenografts co-engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV-003 clinical development and human proof-of-concept studies in patients with MSLN-expressing cancers.
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Affiliation(s)
- Luigi Grasso
- Navrogen Inc., 1837 University Circle, Cheyney, PA 19319
| | - Qun Jiang
- Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland
| | - Raffit Hassan
- Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland
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Targeting Mesothelin in Solid Tumours: Anti-mesothelin Antibody and Drug Conjugates. Curr Oncol Rep 2023; 25:309-323. [PMID: 36763234 DOI: 10.1007/s11912-023-01367-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2022] [Indexed: 02/11/2023]
Abstract
PURPOSE OF REVIEW This review aims to summarise the pathobiological role of mesothelin and the current data on therapeutic antibodies targeting mesothelin in solid tumours. RECENT FINDINGS High mesothelin expression is restricted to the pericardium, pleura, peritoneum and tunica vaginalis. Mesothelin does not seem to have any normal biological function in adult normal tissues. Mesothelin is highly expressed in mesothelioma, serous ovarian cancer, pancreatic cancer and some gastric cancer and adenocarcinoma of the lung and is responsible for tumour proliferation, metastasis, resistance to chemotherapy or radiation and evasion of immune system. To date, antibody, antibody drug conjugates and bispecific antibodies with immune checkpoints have been investigated in mesothelin expressing malignancies. After a couple of decades of clinical investigation in antibody targeting mesothelin, the therapeutic benefit is relatively modest. Novel delivery of mesothelin targeting agents, more potent payload in antibody drug conjugates and immune checkpoint inhibitor, may improve therapeutic benefit.
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10
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Lee YE, Go GY, Koh EY, Yoon HN, Seo M, Hong SM, Jeong JH, Kim JC, Cho D, Kim TS, Kim SC, Jun E, Jang M. Synergistic therapeutic combination with a CAF inhibitor enhances CAR-NK-mediated cytotoxicity via reduction of CAF-released IL-6. J Immunother Cancer 2023; 11:e006130. [PMID: 36849201 PMCID: PMC9972461 DOI: 10.1136/jitc-2022-006130] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2023] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing. METHODS To overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method. RESULTS Nintedanib blocked the platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRβ+-CAF population area, a potential prognostic/therapeutic marker, was associated with inferior clinical outcomes. CONCLUSION Our strategy against PDGFRβ+-CAF-containing pancreatic cancer allows improvements in the therapy of pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Young Eun Lee
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Korea (the Republic of)
- Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea (the Republic of)
| | - Ga-Yeon Go
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Korea (the Republic of)
| | - Eun-Young Koh
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea (the Republic of)
| | - Han-Na Yoon
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Korea (the Republic of)
| | - Minkoo Seo
- Corporate Research & Development Center, UCI therapeutics, Seoul, Korea (the Republic of)
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Ji Hye Jeong
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea (the Republic of)
| | - Jin-Chul Kim
- Natural Product Research Center, Institute of Natural Products, Korea Institute of Science and Technology, Gangneung, Korea (the Republic of)
| | - Duck Cho
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea (the Republic of)
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea (the Republic of)
| | - Tae Sung Kim
- Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea (the Republic of)
| | - Song Cheol Kim
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (the Republic of)
| | - Eunsung Jun
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea (the Republic of)
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (the Republic of)
| | - Mihue Jang
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Korea (the Republic of)
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Korea (the Republic of)
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11
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Bakun OV, Koval HD, Dudka YA, Oshchepkova IA, Makoviichuk KY. INFLUENCE OF PROBIOTICS ON THE MESOTHELIN LEVEL IN WOMEN WITH ENDOMETRIOSIS ASSOCIATED WITH INFERTILITY IN COMPLEX PREPARATION FOR ASSISTED REPRODUCTIVE TECHNOLOGIES. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2023; 76:2455-2459. [PMID: 38112364 DOI: 10.36740/wlek202311118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
OBJECTIVE The aim: To study the determination of Mesothelin level in women with endometriosis associated with infertility and estimate influence of probiotic on endometriosis according of Mesothelin level in complex preparation before assisted reproductive technologies. PATIENTS AND METHODS Materials and methods: In this study, we conducted a retrospective analysis of the medical records of 40 infertile women who underwent assisted reproductive technologies while also using the probiotic "Femina Probiz." We divided the participants into two groups. The control group comprised 11 women who had tubal infertility due to a previous inflammatory condition but were otherwise found to be in good health through comprehensive clinical and laboratory assessments. These women, aged between 21 and 42 with an average age of 29.75 years, did not use the probiotic "Femina Probiz." The main group consisted of 29 women diagnosed with external genital endometriosis who were undergoing assisted reproductive technologies. Women in the main group received the probiotic "Femina Probiz" from Unic Biotech Ltd, India. They took one tablet twice a day for one month as part of their overall treatment before undergoing assisted reproductive technologies. We measured the Mesothelin levels before and after this preparation phase. This study was conducted at Bukovinian State Medical University and Centre of Reproductive Medicine. It's worth noting that the primary infertility incidence was significantly higher in the main group of patients. RESULTS Results: In the main group, we observed that the Mesothelin level was 0.73±0.01, which was significantly higher than the post-preparation level (0.59±0.01). In contrast, the control group had a Mesothelin level of 0.49±0.01. Interestingly, we noted that the Mesothelin level in patients increased approximately twofold before preparation compared to those who had undergone preparation. This suggests that the use of the probiotic led to a sharp reduction in the elevated Mesothelin levels. Consequently, the significant decrease in Mesothelin levels after using the probiotic indicates its effectiveness and potential utility in the preparation phase of assisted reproductive technologies programs. CONCLUSION Conclusions: The elevated Mesothelin levels indicate a strong association between the pathogenesis of endometriosis and inflammation, as well as damage to the peritoneum. The incorporation of a probiotic as part of a comprehensive preparation regimen prior to assisted reproductive technologies notably enhances the overall health of patients and leads to a reduction in Mesothelin levels. Based on our findings, we highly recommend the inclusion of this probiotic preparation in clinical practice.
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Affiliation(s)
- Oksana V Bakun
- BUKOVINIAN STATE MEDICAL UNIVERSITY, CHERNIVTSI, UKRAINE
| | - Halyna D Koval
- BUKOVINIAN STATE MEDICAL UNIVERSITY, CHERNIVTSI, UKRAINE
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12
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Marimuthu S, Lakshmanan I, Muniyan S, Gautam SK, Nimmakayala RK, Rauth S, Atri P, Shah A, Bhyravbhatla N, Mallya K, Grandgenett PM, Hollingsworth MA, Datta K, Jain M, Ponnusamy MP, Batra SK. MUC16 Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma by Upregulating NRP2-Associated Cell Adhesion. Mol Cancer Res 2022; 20:1208-1221. [PMID: 35533267 PMCID: PMC9635595 DOI: 10.1158/1541-7786.mcr-21-0888] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 03/18/2022] [Accepted: 05/03/2022] [Indexed: 11/16/2022]
Abstract
UNLABELLED Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, as it commonly metastasizes to the liver resulting in an overall poor prognosis. However, the molecular mechanism involved in liver metastasis remains poorly understood. Here, we aimed to identify the MUC16-mediated molecular mechanism of PDAC-liver metastasis. Previous studies demonstrated that MUC16 and its C-terminal (Cter) domain are involved in the aggressiveness of PDAC. In this study, we observed MUC16 and its Cter expression significantly high in human PDAC tissues, PDAC organoids, and metastatic liver tissues, while no expression was observed in normal pancreatic tissues using IHC and immunofluorescence (IFC) analyses. MUC16 knockdown in SW1990 and CD18/HPAF PDAC cells significantly decreased the colony formation, migration, and endothelial/p-selectin binding. In contrast, MUC16-Cter ectopic overexpression showed significantly increased colony formation and motility in MiaPaCa2 pancreatic cancer cells. Interestingly, MUC16 promoted cell survival and colonization in the liver, mimicking an ex vivo environment. Furthermore, MUC16 enhanced liver metastasis in the in vivo mouse model. Our integrated analyses of RNA-sequencing suggested that MUC16 alters Neuropilin-2 (NRP2) and cell adhesion molecules in pancreatic cancer cells. Furthermore, we identified that MUC16 regulated NRP2 via JAK2/STAT1 signaling in PDAC. NRP2 knockdown in MUC16-overexpressed PDAC cells showed significantly decreased cell adhesion and migration. Overall, the findings indicate that MUC16 regulates NRP2 and induces metastasis in PDAC. IMPLICATIONS This study shows that MUC16 plays a critical role in PDAC liver metastasis by mediating NRP2 regulation by JAK2/STAT1 axis, thereby paving the way for future therapy efforts for metastatic PDAC.
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Affiliation(s)
- Saravanakumar Marimuthu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sakthivel Muniyan
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Shailendra K. Gautam
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ashu Shah
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Namita Bhyravbhatla
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kavita Mallya
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Paul M. Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael A. Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kaustubh Datta
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moorthy P. Ponnusamy
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
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13
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Giordano G, Ferioli E, Tafuni A. The Role of Mesothelin Expression in Serous Ovarian Carcinoma: Impacts on Diagnosis, Prognosis, and Therapeutic Targets. Cancers (Basel) 2022; 14:cancers14092283. [PMID: 35565412 PMCID: PMC9103848 DOI: 10.3390/cancers14092283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/27/2022] [Accepted: 04/29/2022] [Indexed: 02/05/2023] Open
Abstract
Mesothelin (MSLN) is a protein expressed in the mesothelial cell lining of the pleura, peritoneum, and pericardium; its biological functions in normal cells are still unknown. Experimental studies using knockout mice have suggested that this molecule does not play an important role in development and reproduction. In contrast, it has been observed that this molecule is produced in abnormal amounts in several malignant neoplasms, such as mesotheliomas and pancreatic adenocarcinomas. Many molecular studies have also demonstrated that mesothelin is overexpressed in HSOCs. Here, we discuss the current knowledge of mesothelin and focus on its role in clinical and pathological diagnoses, as well as its impact on the prognosis of HSOC. Moreover, regarding the binding of MSLN to the ovarian cancer antigen CA125, which has been demonstrated in many studies, we also report on signal transduction pathways that may play an important role in the spread and neoplastic progression of this lethal neoplasm. Given that mesothelin is overexpressed in many solid tumours and has antigenic properties, this molecule could be considered an antigenic target for the treatment of many malignancies. Consequently, we also review the literature to report on mesothelin-targeting therapies for HSOC that have been recently investigated in many clinical studies.
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14
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Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine. Br J Cancer 2021; 126:754-763. [PMID: 34876673 DOI: 10.1038/s41416-021-01658-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 10/30/2021] [Accepted: 11/24/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. METHODS We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.
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15
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Einama T, Yamagishi Y, Takihata Y, Suzuki T, Yamasaki T, Hirose Y, Kobayashi K, Yonamine N, Fujinuma I, Tsunenari T, Koga M, Ishibashi Y, Nagata K, Shiraishi T, Nakazawa A, Iwasaki T, Shinto E, Kato K, Sato K, Ueno H, Kishi Y, Tsuda H. Co-expression of mesothelin and CA125/MUC16 is a prognostic factor for breast cancer, especially in luminal-type breast cancer patients. Biomark Res 2021; 9:78. [PMID: 34715925 PMCID: PMC8555316 DOI: 10.1186/s40364-021-00335-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 10/09/2021] [Indexed: 11/10/2022] Open
Abstract
The expression of mesothelin correlates with a poor prognosis in patients with breast cancer. Since mesothelin plays a role in cancer metastasis in association with CA125, we herein examined the expression of mesothelin and CA125, and the clinicopathological meaning and prognosis of the co-expression of mesothelin and CA125 in breast cancer. Our results showed that among 478 patients, mesothelin and CA125 were co-expressed in 48 (10 %), mesothelin only in 75 (16 %), CA125 only in 217 (45 %), and neither in 234 (49 %). A high correlation was observed between the expression of mesothelin and CA125 (P =0.0004). The co-expression of mesothelin and CA125 correlated with poor patient relapse-free survival (RFS) (P = 0.0001) and was identified as an independent predictor of RFS by Cox's multivariate analysis. In conclusion, this is the first to report the prognostic significance of the co-expression of mesothelin and CA125 in breast cancer. The co-expression of mesothelin and CA125 may be clinically useful for prognostication after surgical therapy in patients with breast cancer.
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Affiliation(s)
- Takahiro Einama
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan.
| | - Yoji Yamagishi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan.,Department of Surgery Basic Pathology, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Yasuhiro Takihata
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Takafumi Suzuki
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Tamio Yamasaki
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Yuichi Hirose
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Kazuki Kobayashi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Naoto Yonamine
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Ibuki Fujinuma
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Takazumi Tsunenari
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Makiko Koga
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Yusuke Ishibashi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Ken Nagata
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Takehiro Shiraishi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Akiko Nakazawa
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Toshimitsu Iwasaki
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Eiji Shinto
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Kimi Kato
- Department of Surgery Basic Pathology, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Kimiya Sato
- Department of Surgery Basic Pathology, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
| | - Hitoshi Tsuda
- Department of Surgery Basic Pathology, National Defense Medical College, 3-2 Namiki, 359-8513, Tokorozawa, Saitama, Japan
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16
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Javadi J, Görgens A, Vanky H, Gupta D, Hjerpe A, EL-Andaloussi S, Hagey D, Dobra K. Diagnostic and Prognostic Utility of the Extracellular Vesicles Subpopulations Present in Pleural Effusion. Biomolecules 2021; 11:1606. [PMID: 34827604 PMCID: PMC8615485 DOI: 10.3390/biom11111606] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/18/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are released by all cells into the extracellular matrix and body fluids, where they play important roles in intercellular communication and matrix remodeling in various pathological conditions. Malignant pleural mesothelioma (MPM) is a primary tumor of mesothelial origin, predominantly related to asbestos exposure. The detection of MPM at an early stage and distinguishing it from benign conditions and metastatic adenocarcinomas (AD) is sometimes challenging. Pleural effusion is often the first available biological material and an ideal source for characterizing diagnostic and prognostic factors. Specific proteins have previously been identified as diagnostic markers in effusion, but it is not currently known whether these are associated with vesicles or released in soluble form. Here, we study and characterize tumor heterogeneity and extracellular vesicle diversity in pleural effusion as diagnostic or prognostic markers for MPM. We analyzed extracellular vesicles and soluble proteins from 27 pleural effusions, which were collected and processed at the department of pathology and cytology at Karolinska University Hospital, representing three different patient groups, MPM (n = 9), benign (n = 6), and AD (n = 12). The vesicles were fractionated into apoptotic bodies, microvesicles, and exosomes by differential centrifugation and characterized by nanoparticle tracking analysis and Western blotting. Multiplex bead-based flow cytometry analysis showed that exosomal markers were expressed differently on EVs present in different fractions. Further characterization of exosomes by a multiplex immunoassay (Luminex) showed that all soluble proteins studied were also present in exosomes, though the ratio of protein concentration present in supernatant versus exosomes varied. The proportion of Angiopoietin-1 present in exosomes was generally higher in benign compared to malignant samples. The corresponding ratios of Mesothelin, Galectin-1, Osteopontin, and VEGF were higher in MPM effusions compared to those in the benign group. These findings demonstrate that relevant diagnostic markers can be recovered from exosomes.
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Affiliation(s)
- Joman Javadi
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden; (H.V.); (A.H.); (K.D.)
| | - André Görgens
- Division of BCM, Department of Laboratory Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden; (A.G.); (D.G.); (S.E.-A.); (D.H.)
| | - Hanna Vanky
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden; (H.V.); (A.H.); (K.D.)
| | - Dhanu Gupta
- Division of BCM, Department of Laboratory Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden; (A.G.); (D.G.); (S.E.-A.); (D.H.)
| | - Anders Hjerpe
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden; (H.V.); (A.H.); (K.D.)
| | - Samir EL-Andaloussi
- Division of BCM, Department of Laboratory Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden; (A.G.); (D.G.); (S.E.-A.); (D.H.)
| | - Daniel Hagey
- Division of BCM, Department of Laboratory Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden; (A.G.); (D.G.); (S.E.-A.); (D.H.)
| | - Katalin Dobra
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden; (H.V.); (A.H.); (K.D.)
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17
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Mashayekhi V, Mocellin O, Fens MH, Krijger GC, Brosens LA, Oliveira S. Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma. Theranostics 2021; 11:9022-9037. [PMID: 34522225 PMCID: PMC8419040 DOI: 10.7150/thno.60350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 07/12/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer due to the relatively late diagnosis and the limited therapeutic options. Current treatment regimens mainly comprise the cytotoxic agents gemcitabine and FOLFIRINOX. These compounds have shown limited efficacy and severe side effects, highlighting the necessity for earlier detection and the development of more effective, and better-tolerated treatments. Although targeted therapies are promising for the treatment of several types of cancer, identification of suitable targets for early diagnosis and targeted therapy of PDAC is challenging. Interestingly, several transmembrane proteins are overexpressed in PDAC cells that show low expression in healthy pancreas and may therefore serve as potential targets for treatment and/or diagnostic purposes. In this review we describe the 11 most promising transmembrane proteins, carefully selected after a thorough literature search. Favorable features and potential applications of each target, as well as the results of the preclinical and clinical studies conducted in the past ten years, are discussed in detail.
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Affiliation(s)
- Vida Mashayekhi
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
| | - Orsola Mocellin
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
| | - Marcel H.A.M. Fens
- Pharmaceutics, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Gerard C. Krijger
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, the Netherlands
| | - Lodewijk A.A. Brosens
- Department of Pathology, University Medical Center Utrecht, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, the Netherlands
| | - Sabrina Oliveira
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
- Pharmaceutics, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
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18
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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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19
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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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20
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Ballester B, Milara J, Montero P, Cortijo J. MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway. Int J Mol Sci 2021; 22:ijms22126502. [PMID: 34204432 PMCID: PMC8235375 DOI: 10.3390/ijms22126502] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/30/2021] [Accepted: 06/15/2021] [Indexed: 12/16/2022] Open
Abstract
Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients (n = 20) compared with healthy subjects (n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-β1-induced fibrotic processes such as mesenchymal/ myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as fibroblast proliferation. SiRNA-MUC16 transfection also decreased the TGF-β1-induced SMAD3 phosphorylation, thus inhibiting the Smad Binding Element activation. Immunoprecipitation assays and confocal immunofluorescence showed the formation of a protein complex between MUC16/p-SMAD3 in the cell membrane after TGF-β1 stimulation. This study shows that MUC16 is overexpressed in IPF and collaborates with the TGF-β1 canonical pathway to induce fibrotic processes. Therefore, direct or indirect targeting of MUC16 could be a potential drug target for human IPF.
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Affiliation(s)
- Beatriz Ballester
- Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, 85764 Munich, Germany
- CIBERES, Health Institute Carlos III, 46010 Valencia, Spain;
- Correspondence: (B.B.); (J.M.); Tel.: +34-605148470 (B.B.); +34-963864631 (J.M.)
| | - Javier Milara
- CIBERES, Health Institute Carlos III, 46010 Valencia, Spain;
- Pharmacy Unit, General University Hospital, 46010 Valencia, Spain
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
- Correspondence: (B.B.); (J.M.); Tel.: +34-605148470 (B.B.); +34-963864631 (J.M.)
| | - Paula Montero
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Julio Cortijo
- CIBERES, Health Institute Carlos III, 46010 Valencia, Spain;
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
- Research and Teaching Unit, University General Hospital Consortium, 46010 Valencia, Spain
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21
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Fujii Y, Kamachi H, Matsuzawa F, Mizukami T, Kobayashi N, Fukai M, Taketomi A. Early administration of amatuximab, a chimeric high-affinity anti-mesothelin monoclonal antibody, suppresses liver metastasis of mesothelin-expressing pancreatic cancer cells and enhances gemcitabine sensitivity in a xenograft mouse model. Invest New Drugs 2021; 39:1256-1266. [PMID: 33905019 DOI: 10.1007/s10637-021-01118-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/15/2021] [Indexed: 01/11/2023]
Abstract
Amatuximab is a promising therapeutic antibody targeting mesothelin, a 40-kDa glycoprotein that is highly expressed in pancreatic cancer. We investigated the effectiveness of early amatuximab treatment, imitating an adjuvant chemotherapy setting, and combination therapy with amatuximab and gemcitabine in liver metastasis of pancreatic cancer. Liver metastasis mouse models were established in 8-week-old male BALB/c nu/nu mice using the hemisplenic injection method. Tridaily amatuximab monotherapy or combination with gemcitabine was administered to the liver metastasis mouse model before metastatic lesions had formed huge masses. Gaussia luciferase-transfected AsPC-1 was used as a mesothelin-overexpressing pancreatic cancer cell line. The amount of liver metastases and the serum luciferase activity were significantly lower in the treatment groups than those in the control IgG group. Notably, the anti-tumor activity of gemcitabine was synergically enhanced by combination therapy with amatuximab. Furthermore, western blotting revealed that the high expression of phosphorylated c-Met and AKT in liver metastatic lesions treated with gemcitabine monotherapy was canceled by its combination with amatuximab. This result indicated that the observed synergic therapeutic effect may have occurred as a result of the inhibitory effect of amatuximab on the phosphorylation of c-Met and AKT, which were promoted by exposure to GEM. In conclusion, our study revealed that early administration of amatuximab alone or in combination with GEM significantly suppressed the liver metastases of mesothelin-expressing pancreatic cancer cells. A phase II clinical trial of amatuximab as part of an adjuvant chemotherapy regimen for resected pancreatic cancer is expected.
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Affiliation(s)
- Yuki Fujii
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Hirofumi Kamachi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan.
| | - Fumihiko Matsuzawa
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Tatsuzo Mizukami
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
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22
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Kakimoto S, Miyamoto M, Einama T, Takihata Y, Matsuura H, Iwahashi H, Ishibashi H, Sakamoto T, Hada T, Suminokura J, Ito T, Suzuki R, Suzuki A, Takano M. Significance of mesothelin and CA125 expression in endometrial carcinoma: a retrospective analysis. Diagn Pathol 2021; 16:28. [PMID: 33832498 PMCID: PMC8034188 DOI: 10.1186/s13000-021-01093-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 03/30/2021] [Indexed: 11/29/2022] Open
Abstract
Background This study aimed to investigate the association between clinicopathologic factors, mesothelin, and cancer antigen (CA) 125 in endometrial carcinoma. Methods Between 1989 and 2017, patients with endometrial carcinoma who underwent total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either or both immunochemical expression of mesothelin and CA125 and clinicopathological features were retrospectively examined. Results Among 485 patients, 171 were positive for mesothelin, 368 were positive for CA125, and 167 were positive for mesothelin and CA125. The expression of mesothelin and CA125 was positively correlated (p < 0.01). More patients with mesothelin expression showed myometrial invasion of more than 50% (p = 0.028) and positive lymphovascular invasion (p = 0.027). Similarly, more patients with co-expression of mesothelin and CA125 had myometrial invasion of more than 50% (p = 0.016) and positive lymphovascular invasion (p = 0.02). Patients with mesothelin expression and co-expression of mesothelin and CA125 demonstrated worse progression-free survival (PFS) and overall survival (OS). In the multivariate analysis, mesothelin expression and co-expression were poor prognostic factors for PFS (mesothelin expression: hazard ratio [HR] = 2.14, p < 0.01; co-expression: HR = 2.19, p < 0.01) and OS (mesothelin expression: HR = 2.18, p < 0.01; co-expression: HR = 2.22, p < 0.01). Conclusions Mesothelin expression and co-expression might be associated with tumor aggressiveness and poor prognosis in patients with endometrial carcinoma. Persons with mesothelin-expressing endometrial cancers present a particularly high medical unmet need.
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Affiliation(s)
- Soichiro Kakimoto
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Morikazu Miyamoto
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan.
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Yasuhiro Takihata
- Department of Surgery, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hiroko Matsuura
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hideki Iwahashi
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hiroki Ishibashi
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Takahiro Sakamoto
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Taira Hada
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Jin Suminokura
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Tsubasa Ito
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Rie Suzuki
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Ayako Suzuki
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan.,Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo, 113-8431, Japan
| | - Masashi Takano
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
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23
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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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24
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Review of clinical and emerging biomarkers for early diagnosis and treatment management of pancreatic cancer: towards personalised medicine. JOURNAL OF RADIOTHERAPY IN PRACTICE 2021. [DOI: 10.1017/s1460396921000182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Abstract
Background:
Pancreatic cancer is the 12th most commonly diagnosed cancer and the 3rd leading cause of cancer mortality and accounts for approximately 2·7% of all newly diagnosed cancer cases and 6·4% of all cancer mortalities in Canada. It has a very poor survival rate mainly due to the difficulty of detecting the disease at an early stage. Consequently, in the advancement of disease management towards the concept of precision medicine that takes individual patient variabilities into account, several investigators have focused on the identification of effective clinical biomarkers with high specificity and sensitivity, capable of early diagnosis of symptomatic patients and early detection of the disease in asymptomatic individuals at high risk for developing pancreatic cancer.
Materials and methods:
We searched several databases from August to December 2020 for relevant studies published in English between 2000 and 2020 and reporting on biomarkers for the management of pancreatic cancer. In this narrative review paper, we describe 13 clinical and emerging biomarkers for pancreatic cancers used in screening for early detection and diagnosis, to identify patients’ risk for metastatic disease and subsequent relapse, to monitor patient response to specific treatment and to provide clinicians the possibility of prospectively identifying groups of patients who will benefit from a particular treatment.
Conclusions:
Current and emerging biomarkers for pancreatic cancer with high specificity and sensitivity has the potential to account for individual patient variabilities, for early detection of disease before the onset of metastasis to improve treatment outcome and patients’ survival, help screen high-risk populations, predict prognosis, provide accurate information of patient response to specific treatment and improve patients monitoring during treatment. Thus, the future holds promise for the use of effective clinical biomarkers or a panel of biomarkers for personalised patient-specific targeted medicine for pancreatic cancer.
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25
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Takihata Y, Einama T, Kobayashi K, Suzuki T, Yonamine N, Fujinuma I, Tsunenari T, Yamagishi Y, Iwasaki T, Miyata Y, Shinto E, Ogata S, Tsujimoto H, Ueno H, Kishi Y. Different role of MSLN and CA125 co-expression as a prognostic predictor between perihilar and distal bile duct carcinoma. Oncol Lett 2021; 21:414. [PMID: 33841575 PMCID: PMC8020376 DOI: 10.3892/ol.2021.12675] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/15/2021] [Indexed: 01/03/2023] Open
Abstract
Recent studies have suggested that the interaction of mesothelin (MSLN) and cancer antigen 125 (CA125) enhances tumor metastases. The aim of the present study was to clarify the impact of MSLN and CA125 co-expression on the prognosis of patients with extrahepatic bile duct carcinoma (BDC). Tissue samples from patients who underwent surgical resection between 2007 and 2015 for perihilar or distal BDC were immunohistochemically examined. The expression levels of MSLN and CA125 in tumor cells were analyzed. The expression in <50% and ≥50% of the total tumor cells were defined as low- and high-level expression, respectively. Tissue samples were obtained from 31 patients with perihilar BDC and 43 patients with distal BDC. Lymph node metastases were associated with MSLN and CA125 co-expression in patients with perihilar BDC (P=0.002), while there was no association between lymph node metastasis and co-expression in patients with distal BDC (P=0.362). MSLN and CA125 co-expression was associated with a worse overall survival rate in patients with perihilar BDC (5-year overall survival rate, co-expression positive vs. negative, 24 vs. 63%; P=0.038). To the best of our knowledge, the present study is the first to report an association between co-expression of MSLN and CA125 with a poor prognosis in patients with perihilar BDC. The current findings suggested that the significance of co-expression differed according to the BDC location.
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Affiliation(s)
- Yasuhiro Takihata
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Kazuki Kobayashi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Takafumi Suzuki
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Naoto Yonamine
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Ibuki Fujinuma
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Takazumi Tsunenari
- 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
| | - Toshimitsu Iwasaki
- 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
| | - Eiji Shinto
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Sho Ogata
- Department of Pathology and Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Hironori Tsujimoto
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Hideki Ueno
- 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
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26
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Liu X, Li Z, Wang Y. Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer. Adv Biol (Weinh) 2021; 5:e1900236. [PMID: 33729700 DOI: 10.1002/adbi.201900236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 08/19/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a highly aggressive malignancy with an overall 5-year survival rate of <6% due to therapeutic resistance and late-stage diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030. Currently, the treatment options for pancreatic cancer are limited. This disease is usually diagnosed at a late stage, which prevents curative surgical resection. Chemotherapy is the most frequently used approach for pancreatic cancer treatment and has limited effects. In many other cancer types, targeted therapy and immunotherapy have made great progress and have been shown to be very promising prospects; these treatments also provide hope for pancreatic cancer. The need for research on targeted therapy and immunotherapy is pressing due to the poor prognosis of pancreatic cancer, and in recent years, there have been some breakthroughs for targeted therapy and immunotherapy in pancreatic cancer. This review summarizes the current preclinical and clinical studies of targeted therapy and immunotherapy for pancreatic cancer and ends by describing the challenges and outlook.
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Affiliation(s)
- Xiaoxiao Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhang Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuexiang Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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27
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Javadrashid D, Baghbanzadeh A, Hemmat N, Hajiasgharzadeh K, Nourbakhsh NS, Lotfi Z, Baradaran B. Envisioning the immune system to determine its role in pancreatic ductal adenocarcinoma: Culprit or victim? Immunol Lett 2021; 232:48-59. [PMID: 33647329 DOI: 10.1016/j.imlet.2021.02.009] [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] [Received: 11/14/2020] [Revised: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 12/16/2022]
Abstract
Pancreatic ductal adenocarcinoma has a poor 5-year survival rate that makes it one of the most fatal human malignancies. Unfortunately, despite the serious improvement in the survival of most cancers, there has been a minor advance in pancreatic cancer (PC). Major advances in PC treatment have been assessed over the bygone twenty-year time span, yet some complications make the survival of the patients shorter. Getting to know the PC tumor microenvironment (TME) and the immunosuppression that happens during the pathogenesis of this malignancy could be a great help to understand the nature of the immune system and find better treatment modalities based on it. Although many immune cells are present in PC, immunosuppression of the TME leads to severe immune dysfunction in the patients, therefore immune effectors fail to do their functions. Lately, immunotherapy has been presented as one of the promising treatment strategies for different malignancies including hepatocellular carcinoma, melanoma, non-small cell lung cancer, and kidney cancer. In PC, there has been shown promising results centered around the TME, immune checkpoint inhibitors, cancer vaccines, and other approaches especially when used as combinational therapy. Here we dig a little deeper into the role of the immune system and possible therapeutic options in the treatment of PC.
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Affiliation(s)
- Darya Javadrashid
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Ziba Lotfi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.
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28
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Matsuzawa F, Kamachi H, Mizukami T, Einama T, Kawamata F, Fujii Y, Fukai M, Kobayashi N, Hatanaka Y, Taketomi A. Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells. BMC Cancer 2021; 21:200. [PMID: 33637083 PMCID: PMC7912898 DOI: 10.1186/s12885-020-07722-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.
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Affiliation(s)
- Fumihiko Matsuzawa
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Hirofumi Kamachi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
| | - Tatsuzo Mizukami
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan
| | - Futoshi Kawamata
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yuki Fujii
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yutaka Hatanaka
- Research Division of Companion Diagnostics, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
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Banville AC, Wouters MCA, Oberg AL, Goergen KM, Maurer MJ, Milne K, Ashkani J, Field E, Ghesquiere C, Jones SJM, Block MS, Nelson BH. Co-expression patterns of chimeric antigen receptor (CAR)-T cell target antigens in primary and recurrent ovarian cancer. Gynecol Oncol 2020; 160:520-529. [PMID: 33342620 DOI: 10.1016/j.ygyno.2020.12.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/06/2020] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Chimeric antigen receptor (CAR)-T cell strategies ideally target a surface antigen that is exclusively and uniformly expressed by tumors; however, no such antigen is known for high-grade serous ovarian carcinoma (HGSC). A potential solution involves combinatorial antigen targeting with AND or OR logic-gating. Therefore, we investigated co-expression of CA125, Mesothelin (MSLN) and Folate Receptor alpha (FOLRA) on individual tumor cells in HGSC. METHODS RNA expression of CA125, MSLN, and FOLR1 was assessed using TCGA (HGSC) and GTEx (healthy tissues) databases. Antigen expression profiles and CD3+, CD8+ and CD20+ tumor-infiltrating lymphocyte (TIL) patterns were assessed in primary and recurrent HGSC by multiplex immunofluorescence and immunohistochemistry. RESULTS At the transcriptional level, each antigen was overexpressed in >90% of cases; however, MSLN and FOLR1 showed substantial expression in healthy tissues. At the protein level, CA125 was expressed by the highest proportion of cases and tumor cells per case, followed by MSLN and FOLRA. The most promising pairwise combination was CA125 and/or MSLN (OR gate), with 51.9% of cases containing ≥90% of tumor cells expressing one or both antigens. In contrast, only 5.8% of cases contained ≥90% of tumor cells co-expressing CA125 and MSLN (AND gate). Antigen expression patterns showed modest correlations with TIL. Recurrent tumors retained expression of all three antigens and showed increased TIL densities. CONCLUSIONS An OR-gated CAR-T cell strategy against CA125 and MSLN would target the majority of tumor cells in most cases. Antigen expression and T-cell infiltration patterns are favorable for this strategy in primary and recurrent disease.
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Affiliation(s)
- Allyson C Banville
- Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | | | - Ann L Oberg
- Division of Biomedical Statistics & Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Krista M Goergen
- Division of Biomedical Statistics & Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Matthew J Maurer
- Division of Biomedical Statistics & Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Katy Milne
- Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada
| | - Jahanshah Ashkani
- Genome Sciences Centre, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada
| | - Emma Field
- Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada
| | | | - Steven J M Jones
- Genome Sciences Centre, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada
| | - Matthew S Block
- Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Brad H Nelson
- Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8P 3E6, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
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30
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Molecular targets for diagnostic and intraoperative imaging of pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX treatment. Sci Rep 2020; 10:16211. [PMID: 33004930 PMCID: PMC7529886 DOI: 10.1038/s41598-020-73242-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 07/14/2020] [Indexed: 12/17/2022] Open
Abstract
Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin αvβ6, carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5), mesothelin, prostate-specific membrane antigen (PSMA), urokinase-type plasminogen activator receptor, fibroblast activating receptor, integrin α5 subunit and epidermal growth factor receptor was evaluated using immunohistochemistry. Immunoreactivity was determined using the semiquantitative H-score. Resection specimens from patients after neoadjuvant FOLFIRINOX treatment containing PDAC (n = 32), tumor associated pancreatitis (TAP) and TIF (n = 15), normal pancreas parenchyma (NPP) (n = 32) and tumor positive (n = 24) and negative (n = 56) lymph nodes were included. Integrin αvβ6, CEACAM5, mesothelin and PSMA stainings showed significantly higher expression in PDAC compared to TAP and NPP. No expression of αvβ6, CEACAM5 and mesothelin was observed in TIF. Integrin αvβ6 and CEACAM5 allow for accurate metastatic lymph node detection. Targeting integrin αvβ6, CEA, mesothelin and PSMA has the potential to distinguish vital PDAC from fibrotic tissue after neoadjuvant FOLFIRINOX treatment. Integrin αvβ6 and CEACAM5 detect primary tumors and tumor positive lymph nodes.
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31
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Abou-El-Naga AM, Abo El-Khair SM, Mahmoud AZ, Hamza M, Elshazli RM. Association of genetic variants in the 3'-untranslated region of the mesothelin (MSLN) gene with ovarian carcinoma. J Biochem Mol Toxicol 2020; 35:e22637. [PMID: 32997381 DOI: 10.1002/jbt.22637] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/17/2020] [Accepted: 09/16/2020] [Indexed: 12/14/2022]
Abstract
Limited information has been offered regarding the association of mesothelin (MSLN) gene variants at the 3'-untranslated region with the risk of ovarian carcinoma. The primary objective of this work is to assess the impact of the MSLN (rs1057147 and rs57272256) variants on the progression of ovarian carcinoma among Egyptian women. The study was conceived based on 127 women diagnosed with ovarian carcinoma and 106 unrelated cancer-free controls. Genomic DNA of these MSLN variants was genotyped utilizing the PCR technique. The frequencies of the MSLN (rs1057147) variant revealed a significant association with increased risk of ovarian carcinoma under allelic and dominant models (P < .05). Nonetheless, ovarian cancer patients with the MSLN (rs57272256) variant did not attain considerable significance under all genetic models (P > .05). Together, our findings suggested that the MSLN (rs1057147) variant was associated with an increased risk of ovarian carcinoma, but not the MSLN (rs57272256) variant.
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Affiliation(s)
| | - Salwa M Abo El-Khair
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ashraf Z Mahmoud
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Mohamed Hamza
- Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Rami M Elshazli
- Department of Biochemistry, Faculty of Physical Therapy, Horus University - Egypt, New Damietta, Egypt
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32
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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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Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors. Biomolecules 2020; 10:biom10070973. [PMID: 32605175 PMCID: PMC7408136 DOI: 10.3390/biom10070973] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/24/2020] [Accepted: 06/26/2020] [Indexed: 12/12/2022] Open
Abstract
Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox’s has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox’s. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.
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Kakimoto S, Miyamoto M, Einama T, Matsuura H, Iwahashi H, Ishibashi H, Sakamoto T, Hada T, Takano M. Co-Expression of Mesothelin and CA125 Is Associated with the Poor Prognosis of Endometrial Serous Carcinoma and Mixed Carcinomas Including Serous Carcinoma. Pathol Oncol Res 2020; 26:2299-2306. [PMID: 32468249 DOI: 10.1007/s12253-020-00823-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 05/14/2020] [Indexed: 12/21/2022]
Abstract
The aim of this study was to investigate the association between the clinicopathologic factors and either expression or co-expression of mesothelin and cancer antigen (CA) 125 in endometrial serous carcinoma and mixed carcinomas including serous carcinoma. Between 1990 and 2017, patients with endometrial serous carcinoma and mixed carcinoma including serous carcinoma treated by total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either expression or co-expression of mesothelin and CA125 was evaluated by immunochemical analysis and the clinico-pathological features were retrospectively examined. Among the 40 patients included, 19, 31, and 18 patients exhibited single positive mesothelin, single positive CA125, and positive co-expression, respectively. The expression of mesothelin and CA125 was observed to be positively associated (p = 0.021). There was no significant association of age and FIGO stage with individual mesothelin or CA125 expression or their co-expression. Overall survival (OS), but not progression-free survivals (PFS), of only mesothelin-positive patients was worse (p = 0.024). Hence, OS and PFS of patients with positive co-expression were worse (PFS: p = 0.043, OS: p = 0.012). In multivariate analysis, single mesothelin expression and single CA125 expression did not lead to worse prognosis. However, positive co-expression was the worst prognostic factor for OS (hazard ratio: 3.32, p = 0.039). Co-expression of mesothelin and CA125 may accurately predict OS in endometrial serous carcinoma and mixed carcinomas including serous carcinoma. Further studies should examine this relationship.
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Affiliation(s)
- Soichiro Kakimoto
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Morikazu Miyamoto
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan.
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hiroko Matsuura
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hideki Iwahashi
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hiroki Ishibashi
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Takahiro Sakamoto
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Taira Hada
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Masashi Takano
- Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
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Li KY, Yuan JL, Trafton D, Wang JX, Niu N, Yuan CH, Liu XB, Zheng L. Pancreatic ductal adenocarcinoma immune microenvironment and immunotherapy prospects. Chronic Dis Transl Med 2020; 6:6-17. [PMID: 32226930 PMCID: PMC7096327 DOI: 10.1016/j.cdtm.2020.01.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Indexed: 02/08/2023] Open
Abstract
The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is non-immunogenic, which consists of the stellate cells, fibroblasts, immune cells, extracellular matrix, and some other immune suppressive molecules. This low tumor perfusion microenvironment with physical dense fibrotic stroma shields PDAC from traditional antitumor therapies like chemotherapy and various strategies that have been proven successful in other types of cancer. Immunotherapy has the potential to treat minimal and residual diseases and prevent recurrence with minimal toxicity, and studies in patients with metastatic and nonresectable disease have shown some efficacy. In this review, we highlighted the main components of the pancreatic tumor microenvironment, and meanwhile, summarized the advances of some promising immunotherapies for PDAC, including checkpoint inhibitors, chimeric antigen receptors T cells, and cancer vaccines. Based on our previous researches, we specifically discussed how granulocyte-macrophage colony stimulating factor based pancreatic cancer vaccine prime the pancreatic tumor microenvironment, and introduced some novel immunoadjuvants, like the stimulator of interferon genes.
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Affiliation(s)
- Ke-Yu Li
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Jia-Long Yuan
- School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Diego Trafton
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Jian-Xin Wang
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Hepatic-biliary-pancreatic Surgery, First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310000, China
| | - Nan Niu
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China
| | - Chun-Hui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Xu-Bao Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lei Zheng
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
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Regzedmaa O, Li Y, Li Y, Zhang H, Wang J, Gong H, Yuan Y, Li W, Liu H, Chen J. Prevalence of DLL3, CTLA-4 and MSTN Expression in Patients with Small Cell Lung Cancer. Onco Targets Ther 2019; 12:10043-10055. [PMID: 31819500 PMCID: PMC6877464 DOI: 10.2147/ott.s216362] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 11/06/2019] [Indexed: 12/25/2022] Open
Abstract
Introduction Immune-based and antibody-drug conjugate therapies have shown promise in the treatment of patients with small cell lung cancer (SCLC). However, better predictive biomarkers are needed for selection of the appropriate SCLC patients for these advanced therapies and also for evaluation of the efficacy of these treatments. Objective The aim of this study was to examine the expression of delta-like protein 3 (DLL3), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and mesothelin (MSTN) in patients with SCLC and compare them with those patients’ clinical characteristics. Methods Immunohistochemical analyses of DLL3, CTLA-4 and MSTN expression were performed in 38 samples from patients with SCLC. Results We found that positive expression in patients of the biomarkers was as follows: for DLL3, 100% (38/38), for CTLA-4, 89.5% (36/38) and for MSTN 81.5% (31/38). The median survival time was 17.9 months in the DLL3 high expression group and 23 months in the DLL3 low expression group. Patients with a high expression of DLL3 showed a poorer prognosis than those with a low expression of DLL3 (HR=3.4; 95% CI, 1.34–8.6; p=0.01). Conclusion The expression of DLL3, CTLA-4 and MSTN was not correlated with patients’ age, sex, smoking status, stage, and tumor metastasis. The fact that there was a higher expression of DLL3, CTLA-4, and MSTN in SCLC suggested that these molecules could be used as predictive biomarkers for SCLC.
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Affiliation(s)
- Orgilmaa Regzedmaa
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Ying Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Yongwen Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Hongbing Zhang
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Jin Wang
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Hao Gong
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Yin Yuan
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Weiting Li
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Hongyu Liu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Jun Chen
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China.,Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
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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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Li T, Li H, Li S, Xu S, Zhang W, Gao H, Xu H, Wu C, Wang W, Yu X, Liu L. Research progress and design optimization of CAR-T therapy for pancreatic ductal adenocarcinoma. Cancer Med 2019; 8:5223-5231. [PMID: 31339230 PMCID: PMC6718528 DOI: 10.1002/cam4.2430] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/05/2019] [Accepted: 07/05/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer with limited treatment options. Chimeric antigen receptor T cells (CAR-T) are genetically engineered T cells that can specifically kill tumor cells without major histocompatibility complex restriction. Encouraging progress in CAR-T therapy for PDAC has been made in preclinical and early phase clinical trials. Challenges in CAR-T therapy for solid tumors still exist, including immunosuppressive microenvironment, interstitial barrier, poor chemotaxis, and the "on-target, off-tumor" effect. Applying neoantigens of PDAC as targets for CAR-T therapy, recognizing the CAR-T subgroup with better antitumor effect, and designing a CAR-T system targeting stroma of PDAC may contribute to develop a powerful CAR-T therapy for PDAC in the future.
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MESH Headings
- Animals
- Antigens, Neoplasm
- Biomarkers, Tumor
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/therapy
- Chemotaxis/immunology
- Humans
- Immunotherapy, Adoptive/adverse effects
- Immunotherapy, Adoptive/methods
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/therapy
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/metabolism
- Research
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Tumor Microenvironment/immunology
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Affiliation(s)
- Tianjiao Li
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Hao Li
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Shuo Li
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Shuaishuai Xu
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Wuhu Zhang
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Heli Gao
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Huaxiang Xu
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Chuntao Wu
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Wenquan Wang
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Xianjun Yu
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Liang Liu
- Department of Pancreatic Surgery, Shanghai Cancer CentreFudan UniversityShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
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Kim H, Chung Y, Paik SS, Jang K, Shin SJ. Mesothelin expression and its prognostic role according to microsatellite instability status in colorectal adenocarcinoma. Medicine (Baltimore) 2019; 98:e16207. [PMID: 31261569 PMCID: PMC6616341 DOI: 10.1097/md.0000000000016207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The cell-surface glycoprotein, mesothelin, is normally present on mesothelial cells. Overexpression of mesothelin has been reported in many tumors and is correlated with poor outcome. We investigated the clinicopathologic significance of mesothelin expression in colorectal adenocarcinoma with microsatellites instability (MSI) status.Mesothelin expression was evaluated immunohistochemically in tissue microarray blocks from 390 colorectal adenocarcinoma samples. Mesothelin expression was interpreted according to the intensity and extent. A score of 2 was considered high expression. We analyzed the correlation between mesothelin expression and clinicopathologic characteristics.High mesothelin expression was observed in 177 (45.4%) out of 390 colorectal adenocarcinoma samples and was significantly associated with high histologic grade (P = .037), lymphatic invasion (P = .028), lymph node metastasis (P = .028), and high AJCC stage (P = .026). Kaplan-Meier survival curves revealed no significant difference between patients with high mesothelin expression and patients with low mesothelin expression in both recurrence-free survival (RFS) and cancer-specific survival (P = .609 and P = .167, respectively). In subgroup survival analyses, high mesothelin expression was associated with poor RFS in the MSI-High group of colorectal adenocarcinoma (P = .004).High mesothelin expression was significantly associated with aggressive phenotypes and poor patient outcome in MSI-High colorectal adenocarcinoma.
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Pandey V, Storz P. Targeting the tumor microenvironment in pancreatic ductal adenocarcinoma. Expert Rev Anticancer Ther 2019; 19:473-482. [PMID: 31148495 PMCID: PMC6548630 DOI: 10.1080/14737140.2019.1622417] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/20/2019] [Indexed: 12/18/2022]
Abstract
Introduction: The dismally slow improvement in patient survival over the years for pancreatic cancer patients is mainly due to two factors: the late diagnosis, at which point the disease is spread to distant organs; and the fact that tumor cells are surrounded by a dense, highly immunosuppressive microenvironment. The tumor microenvironment not only shields pancreatic cancer cells from chemotherapy but also leaves it unsusceptible to various immunotherapeutic strategies that have been proven successful in other types of cancer. Areas covered: This review highlights the main components of the pancreatic tumor microenvironment, how they cross-talk with each other to generate stroma and promote tumor growth. Additionally, we discuss the most promising treatment targets in the microenvironment whose modulation can be robustly tested in combination with standard of care chemotherapy. Currently, active clinical trials for pancreatic cancer involving components of the microenvironment are also listed. Expert opinion: Although immunotherapeutic approaches involving checkpoint inhibition are being pursued enthusiastically, there is still more work to be done with several other emerging immune targets that could provide therapeutic benefit.
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Affiliation(s)
- Veethika Pandey
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second most common cause of cancer-related death in the United States by 2030. So far surgery remains the only curative option for pancreatic cancer, but fewer than 20% of patients have surgically resectable disease. Furthermore, pancreatic cancer exhibits a remarkable resistance to established therapeutic options, including chemotherapy, radiotherapy, and targeted therapy, because pancreatic cancer exhibits numerous mechanisms of resistance like genetic and epigenetic alterations and a complex and dense tumor microenvironment. The tumor microenvironment is populated with different types of immune cells that play a critical role in therapy resistance, tumor progression, and carcinogenesis. Cancer immunotherapy has now been recognized as the fourth pillar of cancer care and a number of preclinical and clinical studies have been conducted for pancreatic cancer. Targeting and modulating the tumor immune microenvironment could not only switch the immune system toward anti-cancer, but also may improve sensitivity toward established chemotherapy. In this review, we discuss both preclinical and clinical studies on pancreatic cancer immunotherapy with natural killer cells, dendritic cells, and chimeric antigen receptor T cells. Furthermore, we summarize strategies for reprogramming the tumor immune microenvironment by targeting macrophages and stromal cell factors in pancreatic cancer. The development of systemic therapies is essential for improving the outcomes of pancreatic cancer patients, and cancer immunotherapy would improve effectiveness of other established therapeutic options, which might together improve the prognosis of pancreatic tumors.
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Jiang J, Zhou H, Ni C, Hu X, Mou Y, Huang D, Yang L. Immunotherapy in pancreatic cancer: New hope or mission impossible? Cancer Lett 2019; 445:57-64. [DOI: 10.1016/j.canlet.2018.10.045] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 09/29/2018] [Accepted: 10/10/2018] [Indexed: 12/17/2022]
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Leal AD, Krishnamurthy A, Head L, Messersmith WA. Antibody drug conjugates under investigation in phase I and phase II clinical trials for gastrointestinal cancer. Expert Opin Investig Drugs 2018; 27:901-916. [PMID: 30359534 DOI: 10.1080/13543784.2018.1541085] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Antibody drug conjugates (ADCs) represent a developing class of anticancer therapeutics which are designed to selectively deliver a cytotoxic payload to tumors, while limiting systemic toxicity to healthy tissues. There are several ADCs which are currently in various stages of clinical development for the treatment of gastrointestinal malignancies. AREAS COVERED We discuss the biologic rationale and review the clinical experience with ADCs in the treatment of gastrointestinal malignancies, summarizing the pre-clinical and phase I/II clinical trial data that have been completed or are ongoing. EXPERT OPINION While there have been significant advances in the development of ADCs since they were first introduced, several challenges remain. These challenges include (i) the selection of an ideal antigen target which is tumor specific and internalized upon binding, (ii) selection of an antibody which has high affinity for its antigen target and low immunogenicity, (iii) selection of a potent payload which is cytotoxic at sub-nanomolar concentrations, and (iv) optimal design of a linker to confer ADC stability with limited off-site toxicity. Efforts are ongoing to address these issues and innovate the ADC technology to improve the safety and efficacy of these agents.
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Affiliation(s)
- Alexis D Leal
- a Division of Medical Oncology , University of Colorado , Aurora , CO , USA
| | | | - Lia Head
- b Department of Internal Medicine , University of Colorado , Aurora , CO , USA
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Nahm CB, Turchini J, Jamieson N, Moon E, Sioson L, Itchins M, Arena J, Colvin E, Howell VM, Pavlakis N, Clarke S, Samra JS, Gill AJ, Mittal A. Biomarker panel predicts survival after resection in pancreatic ductal adenocarcinoma: A multi-institutional cohort study. Eur J Surg Oncol 2018; 45:218-224. [PMID: 30348604 DOI: 10.1016/j.ejso.2018.10.050] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 09/26/2018] [Accepted: 10/05/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Up to 60% of patients who undergo curative-intent pancreatic ductal adenocarcinoma (PDAC) resection experience disease recurrence within six months. We recently published a systematic review of prognostic immunohistochemical biomarkers in PDAC and shortlisted a panel of those reported with the highest level of evidence, including p53, p16, Ca-125, S100A4, FOXC1, EGFR, mesothelin, CD24 and UPAR. This study aims to discover and validate the prognostic significance of a combinatorial panel of tumor biomarkers in patients with resected PDAC. METHODS Patients who underwent PDAC resection were included from a single institution discovery cohort and a multi-institutional validation cohort. Tumors in the discovery cohort were stained immunohistochemically for all nine shortlisted biomarkers. Biomarkers significantly associated with overall survival (OS) were reevaluated as a combinatorial panel in both discovery and validation cohorts for its prognostic significance. RESULTS 224 and 191 patients were included in the discovery and validation cohorts, respectively. In both cohorts, S100A4, Ca-125 and mesothelin expression were associated with shorter OS. In both cohorts, the number of these biomarkers expressed was significantly associated with OS (discovery cohort 36.8 vs. 26.4 vs 16.3 vs 12.8 months, P < 0.001; validation cohort 25.2 vs 18.3 vs 13.6 vs 11.9 months, P = 0.008 for expression of zero, one, two and three biomarkers, respectively). On multivariable analysis, expression of at least one of three biomarkers was independently associated with shorter OS. CONCLUSION Combinations of S100A4, Ca-125 and mesothelin expression stratify survival after resection of localized PDAC. Co-expression of all three biomarkers is associated with the poorest prognostic outcome.
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Affiliation(s)
- Christopher B Nahm
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, St. Leonards, NSW Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia
| | - John Turchini
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Cancer Diagnosis and Pathology, Kolling Institute, University of Sydney, Sydney, NSW, Australia
| | - Nigel Jamieson
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Elizabeth Moon
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia
| | - Loretta Sioson
- Cancer Diagnosis and Pathology, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia
| | - Malinda Itchins
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW, Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia
| | - Jennifer Arena
- Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW, Australia; Australian Pancreatic Centre, Royal North Shore Hospital, St. Leonards, NSW, Australia
| | - Emily Colvin
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia
| | - Viive M Howell
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia
| | - Nick Pavlakis
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW, Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia; Australian Pancreatic Centre, Royal North Shore Hospital, St. Leonards, NSW, Australia
| | - Stephen Clarke
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW, Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia; Australian Pancreatic Centre, Royal North Shore Hospital, St. Leonards, NSW, Australia
| | - Jaswinder S Samra
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, St. Leonards, NSW Australia; Sydney Vital, Kolling Institute, Sydney, NSW, Australia; Australian Pancreatic Centre, Royal North Shore Hospital, St. Leonards, NSW, Australia; Faculty of Medical and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Anthony J Gill
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Cancer Diagnosis and Pathology, Kolling Institute, University of Sydney, Sydney, NSW, Australia; Australian Pancreatic Centre, Royal North Shore Hospital, St. Leonards, NSW, Australia; Faculty of Medical and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Anubhav Mittal
- The University of Sydney Northern Clinical School, Sydney, NSW, Australia; Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, St. Leonards, NSW Australia; Australian Pancreatic Centre, Royal North Shore Hospital, St. Leonards, NSW, Australia; Faculty of Medical and Health Sciences, Macquarie University, Sydney, NSW, Australia.
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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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Xu JW, Wang L, Cheng YG, Zhang GY, Hu SY, Zhou B, Zhan HX. Immunotherapy for pancreatic cancer: A long and hopeful journey. Cancer Lett 2018; 425:143-151. [PMID: 29605510 DOI: 10.1016/j.canlet.2018.03.040] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 02/28/2018] [Accepted: 03/26/2018] [Indexed: 12/11/2022]
Abstract
Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials. The current review describes the roles of immune cells and the immunosuppressive microenvironment in the development of pancreatic cancer, as well as the preclinical and clinical outcomes and benefits of recent immunotherapeutic approaches, which may help us further disclose the mechanisms of pancreatic cancer progression and the dialectical views of feasibility and effectiveness of immunotherapy in treatment of pancreatic cancer.
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Affiliation(s)
- Jian-Wei Xu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Lei Wang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Yu-Gang Cheng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Guang-Yong Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - San-Yuan Hu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Bin Zhou
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266003, China.
| | - Han-Xiang Zhan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China.
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He J, Zhang Z, Lv S, Liu X, Cui L, Jiang D, Zhang Q, Li L, Qin W, Jin H, Qian Q. Engineered CAR T cells targeting mesothelin by piggyBac transposon system for the treatment of pancreatic cancer. Cell Immunol 2018; 329:31-40. [PMID: 29859625 DOI: 10.1016/j.cellimm.2018.04.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 04/11/2018] [Accepted: 04/15/2018] [Indexed: 12/22/2022]
Abstract
Patients with pancreatic cancer have a poor prognosis largely due to the poor efficacy of the available treatment modalities. In this study, we engineered mesothelin-targeting chimeric antigen receptor T cells (mesoCAR T) using the piggyBac transposon based plasmid electroporation technique for specific targeting of pancreatic cancer cells expressing mesothelin. In vitro, mesoCAR T cells exhibited rapid and robust killing effect against ASPC1 cells with high expression levels of mesothelin with high production of IFN-γ; the cytotoxic effect on PANC1 cells with low expressions of mesothelin was relatively attenuated. In the ASPC1 xenograft mice model, mesoCAR T cells significantly suppressed the tumor growth accompanied with higher-level IFN-γ secretion as compared to control T cells. Besides, more mesoCAR T cells differentiated into memory T cells after tumor remission, whilst causing minimal lesions in major organs. Our study suggests promising efficacy of piggyBac transposon-based mesoCAR T cell therapy for pancreatic cancer, which is a potential candidate for clinical translation.
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Affiliation(s)
- Jiangchuan He
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Zhiwei Zhang
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China; Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai 201805, China
| | - Saiqun Lv
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Xiangzhen Liu
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Lianzhen Cui
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Duqing Jiang
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Qi Zhang
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Linfang Li
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Wenxia Qin
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Huajun Jin
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China; Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai 201805, China.
| | - Qijun Qian
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China; Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China; Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai 201805, China.
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Mesothelin-Specific Immune Responses and Targeted Immunotherapy for Mesothelin-Expressing Tumors. EBioMedicine 2017; 24:16-17. [PMID: 28965877 PMCID: PMC5652283 DOI: 10.1016/j.ebiom.2017.09.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 09/24/2017] [Indexed: 11/22/2022] Open
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Xu JY, Ye ZL, Jiang DQ, He JC, Ding YM, Li LF, Lv SQ, Wang Y, Jin HJ, Qian QJ. Mesothelin-targeting chimeric antigen receptor-modified T cells by piggyBac transposon system suppress the growth of bile duct carcinoma. Tumour Biol 2017; 39:1010428317695949. [PMID: 28381173 DOI: 10.1177/1010428317695949] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Chimeric antigen receptor modified T cell-based immunotherapy is revolutionizing the field of cancer treatment. However, its potential in treating bile duct carcinoma has not been fully explored. Herein, we developed the second-generation mesothelin-targeting chimeric antigen receptor-modified T cells with the 4-1BB co-stimulatory module by the piggyBac transposon system. Mesothelin-targeting chimeric antigen receptor was expressed by 66.0% of mesothelin-targeting chimeric antigen receptor-modified T cells post electrophoretic transfection and stimulation with K562-meso cells; the expressions of activation markers were tested by flow cytometry assay and showed greater activation of mesothelin-targeting chimeric antigen receptor-modified T cells than control T cells (CD107α: 71.9% vs 48.6%; CD27: 92.1% vs 61.8%; CD137: 55.5% vs 8.4%; CD28: 98.0% vs 82.1%; CD134: 37.5% vs 10.4%). Furthermore, mesothelin-targeting chimeric antigen receptor-modified T cells exerted cytotoxicity toward mesothelin-expressing EH-CA1b and EH-CA1a cells in an effector-to-target ratio-dependent manner, while leaving mesothelin-negative GSC-SD and EH-GB1 cells and normal liver L02 cells almost unharmed. Mesothelin-targeting chimeric antigen receptor-modified T cells secreted cytokines at higher levels when co-cultured with mesothelin-positive EH-CA1a and EH-CA1b cells than with mesothelin-negative GSC-SD and EH-GB1 cells. Enhanced cytotoxicity and cytokine secretion of mesothelin-targeting chimeric antigen receptor-modified T cells compared to control T cells were also observed when co-cultured with 293-meso cells (interferon γ: 85.1% ± 1.47% vs 8.3% ± 2.50%, p = 0.000; tumor necrosis factor α: 90.9% ± 4.67% vs 18.5% ± 3.62%, p = 0.0004; interleukin 2: 60.8% ± 2.00% vs 15.6% ± 2.06%, p = 0.002; interleukin 6: 6.4% ± 2.95% vs 1.7% ± 0.63%, p = 0.055). In addition, mesothelin-targeting chimeric antigen receptor-modified T cells showed greater inhibitory and proliferative capability than control T cells within EH-CA1a cell xenografts. This study shows the potential of mesothelin-targeting chimeric antigen receptor-modified T cells in treating bile duct carcinoma.
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Affiliation(s)
- Jie-Ying Xu
- 1 Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - Zhen-Long Ye
- 2 Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai, China
| | - Du-Qing Jiang
- 1 Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - Jiang-Chuan He
- 1 Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yong-Mei Ding
- 3 Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai, China
| | - Lin-Fang Li
- 2 Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai, China
| | - Sai-Qun Lv
- 2 Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai, China
| | - Ying Wang
- 2 Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai, China
| | - Hua-Jun Jin
- 2 Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai, China
| | - Qi-Jun Qian
- 1 Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.,2 Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai, China.,3 Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai, China
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