From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma
Abstract
:1. Introduction
2. Role of MSLN in PDAC Progression
2.1. Structure of MSLN and Physiological Functions
2.2. Expression of MSLN in PDAC
2.3. Cell Proliferation and Anti-Apoptosis
2.4. Promoting Tumor Invasion and Metastasis
2.5. Resistance to Chemotherapy
2.6. Genetic Regulation of MSLN Expression in Tumor Cells
3. Predictive Value of MSLN and Anti-MSLN Diagnosis-Dedicated Agents in PDAC
3.1. Predictive Value of MSLN Expression
3.2. SMRP Assay
3.3. Imaging Probes for the Phenotyping of MSLN-Expressing Tumors
4. Anti-MSLN Targeting Drugs in Development
4.1. Antibodies-Based Approach
4.1.1. Immunotoxins SS1P and LMB-100/RG7787
4.1.2. Monoclonal Antibody: Amatuximab
4.1.3. Antibody-Drug Conjugates
4.1.4. 227Th-Radiolabeled Antibody
4.2. Cancer Vaccines
4.3. CAR-T Cells
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ADC | Antibody drug-conjugates |
CAR-T | Chimeric antigen receptor T cells |
Fab | Fragment antigen binding |
GM-CSF | Granulocyte-macrophage colony-stimulating factor |
GPI | Glycosylphosphatidylinositol |
GVAX | GM-CSF gene-transfected tumor cell vaccine |
mAb | Monoclonal antibody |
MAV | Metabolic Active Volume |
MPF | Megakaryocyte-potentiating factor |
MSLN | Mesothelin |
MUC16 | Mucin 16 |
OCT-2 | Homeobox transcription factors POU2F2 |
OS | Overall survival |
PD-1 | programm death 1 |
PD-L1 | programm death ligand 1 |
PD | Progressive disease |
PDAC | Pancreatic ductal adenocarcinoma |
PR | Partial response |
RECIST | Response Evaluation Criteria in Solid Tumors |
RTK | Receptor Tyrosine Kinase |
SD | Stable disease |
SMRP | Serum mesothelin-related peptide |
Tat | Targeted alpha therapy |
References
- Kleeff, J.; Korc, M.; Apte, M.; La Vecchia, C.; Johnson, C.D.; Biankin, A.V.; Neale, R.E.; Tempero, M.; Tuveson, D.A.; Hruban, R.H.; et al. Pancreatic cancer. Nat. Rev. Dis. Primers 2016, 2, 16022. [Google Scholar] [CrossRef]
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30. [Google Scholar] [CrossRef] [PubMed]
- Quante, A.S.; Ming, C.; Rottmann, M.; Engel, J.; Boeck, S.; Heinemann, V.; Westphalen, C.B.; Strauch, K. Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030. Cancer Med. 2016, 5, 2649–2656. [Google Scholar] [CrossRef] [PubMed]
- Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014, 74, 2913–2921. [Google Scholar] [CrossRef] [Green Version]
- Rahn, S.; Zimmermann, V.; Viol, F.; Knaack, H.; Stemmer, K.; Peters, L.; Lenk, L.; Ungefroren, H.; Saur, D.; Schäfer, H.; et al. Diabetes as risk factor for pancreatic cancer: Hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells. Cancer Lett. 2018, 415, 129–150. [Google Scholar] [CrossRef] [PubMed]
- Font-Burgada, J.; Sun, B.; Karin, M. Obesity and Cancer: The Oil that Feeds the Flame. Cell Metab. 2016, 23, 48–62. [Google Scholar] [CrossRef] [Green Version]
- Delitto, D.; Zhang, D.; Han, S.; Black, B.S.; Knowlton, A.E.; Vlada, A.C.; Sarosi, G.A.; Behrns, K.E.; Thomas, R.M.; Lu, X.; et al. Nicotine Reduces Survival via Augmentation of Paracrine HGF-MET Signaling in the Pancreatic Cancer Microenvironment. Clin. Cancer Res. 2016, 22, 1787–1799. [Google Scholar] [CrossRef] [Green Version]
- Zhang, S.; Wang, C.; Huang, H.; Jiang, Q.; Zhao, D.; Tian, Y.; Ma, J.; Yuan, W.; Sun, Y.; Che, X.; et al. Effects of alcohol drinking and smoking on pancreatic ductal adenocarcinoma mortality: A retrospective cohort study consisting of 1783 patients. Sci. Rep. 2017, 7, 9572. [Google Scholar] [CrossRef] [Green Version]
- Pihlak, R.; Valle, J.W.; McNamara, M.G. Germline mutations in pancreatic cancer and potential new therapeutic options. Oncotarget 2017, 8, 73240–73257. [Google Scholar] [CrossRef]
- Hu, C.; Hart, S.N.; Polley, E.C.; Gnanaolivu, R.; Shimelis, H.; Lee, K.Y.; Lilyquist, J.; Na, J.; Moore, R.; Antwi, S.O.; et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA 2018, 319, 2401–2409. [Google Scholar] [CrossRef]
- Orth, M.; Metzger, P.; Gerum, S.; Mayerle, J.; Schneider, G.; Belka, C.; Schnurr, M.; Lauber, K. Pancreatic ductal adenocarcinoma: Biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat. Oncol. 2019, 14, 141. [Google Scholar] [CrossRef] [PubMed]
- Aslan, M.; Shahbazi, R.; Ulubayram, K.; Ozpolat, B. Targeted Therapies for Pancreatic Cancer and Hurdles Ahead. Anticancer Res. 2018, 38, 6591–6606. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Manji, G.A.; Olive, K.P.; Saenger, Y.M.; Oberstein, P. Current and Emerging Therapies in Metastatic Pancreatic Cancer. Clin. Cancer Res. 2017, 23, 1670–1678. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Winter, K.; Talar-Wojnarowska, R.; Dąbrowski, A.; Degowska, M.; Durlik, M.; Gąsiorowska, A.; Głuszek, S.; Jurkowska, G.; Kaczka, A.; Lampe, P.; et al. Diagnostic and therapeutic recommendations in pancreatic ductal adenocarcinoma. Recommendations of the Working Group of the Polish Pancreatic Club. Prz. Gastroenterol. 2019, 14, 1–18. [Google Scholar] [CrossRef]
- Hilmi, M.; Bartholin, L.; Neuzillet, C. Immune therapies in pancreatic ductal adenocarcinoma: Where are we now? World J. Gastroenterol. 2018, 24, 2137–2151. [Google Scholar] [CrossRef]
- Patnaik, A.; Kang, S.P.; Rasco, D.; Papadopoulos, K.P.; Elassaiss-Schaap, J.; Beeram, M.; Drengler, R.; Chen, C.; Smith, L.; Espino, G.; et al. Phase I Study of Pembrolizumab (MK-3475; Anti–PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2015, 21, 4286–4293. [Google Scholar] [CrossRef] [Green Version]
- Le, D.T.; Wang-Gillam, A.; Picozzi, V.; Greten, T.F.; Crocenzi, T.; Springett, G.; Morse, M.; Zeh, H.; Cohen, D.; Fine, R.L.; et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 2015, 33, 1325–1333. [Google Scholar] [CrossRef] [Green Version]
- Hassan, R.; Thomas, A.; Alewine, C.; Le, D.T.; Jaffee, E.M.; Pastan, I. Mesothelin Immunotherapy for Cancer: Ready for Prime Time? J. Clin. Oncol. 2016, 34, 4171–4179. [Google Scholar] [CrossRef] [Green Version]
- 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. 2018, 13, 333–351. [Google Scholar] [CrossRef]
- Ordóñez, N.G. Application of mesothelin immunostaining in tumor diagnosis. Am. J. Surg. Pathol. 2003, 27, 1418–1428. [Google Scholar] [CrossRef] [PubMed]
- Pastan, I.; Hassan, R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 2014, 74, 2907–2912. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chang, K.; Pastan, I.; Willingham, M.C. Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int. J. Cancer 1992, 50, 373–381. [Google Scholar] [CrossRef] [PubMed]
- Chang, K.; Pastan, I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc. Natl. Acad. Sci. USA 1996, 93, 136–140. [Google Scholar] [CrossRef] [Green Version]
- Hassan, R.; Bera, T.; Pastan, I. Mesothelin: A new target for immunotherapy. Clin. Cancer Res. 2004, 10, 3937–3942. [Google Scholar] [CrossRef] [Green Version]
- Hassan, R.; Ho, M. Mesothelin targeted cancer immunotherapy. Eur. J. Cancer 2008, 44, 46–53. [Google Scholar] [CrossRef] [Green Version]
- Sathyanarayana, B.K.; Hahn, Y.; Patankar, M.S.; Pastan, I.; Lee, B. Mesothelin, Stereocilin, and Otoancorin are predicted to have superhelical structures with ARM-type repeats. BMC Struct. Biol. 2009, 9, 1. [Google Scholar] [CrossRef] [Green Version]
- Bera, T.K.; Pastan, I. Mesothelin is not required for normal mouse development or reproduction. Mol. Cell. Biol. 2000, 20, 2902–2906. [Google Scholar] [CrossRef] [Green Version]
- Rump, A.; Morikawa, Y.; Tanaka, M.; Minami, S.; Umesaki, N.; Takeuchi, M.; Miyajima, A. Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J. Biol. Chem. 2004, 279, 9190–9198. [Google Scholar] [CrossRef] [Green Version]
- Gubbels, J.A.A.; Belisle, J.; Onda, M.; Rancourt, C.; Migneault, M.; Ho, M.; Bera, T.K.; Connor, J.; Sathyanarayana, B.K.; Lee, B.; et al. Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol. Cancer 2006, 5, 50. [Google Scholar] [CrossRef] [Green Version]
- Haridas, D.; Ponnusamy, M.P.; Chugh, S.; Lakshmanan, I.; Seshacharyulu, P.; Batra, S.K. MUC16: Molecular analysis and its functional implications in benign and malignant conditions. FASEB J. 2014, 28, 4183–4199. [Google Scholar] [CrossRef] [PubMed]
- Koyama, Y.; Wang, P.; Liang, S.; Iwaisako, K.; Liu, X.; Xu, J.; Zhang, M.; Sun, M.; Cong, M.; Karin, D.; et al. Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J. Clin. Invest. 2017, 127, 1254–1270. [Google Scholar] [CrossRef] [Green Version]
- Muniyan, S.; Haridas, D.; Chugh, S.; Rachagani, S.; Lakshmanan, I.; Gupta, S.; Seshacharyulu, P.; Smith, L.M.; Ponnusamy, M.P.; Batra, S.K. MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism. Genes Cancer 2016, 7, 110–124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Coelho, R.; Marcos-Silva, L.; Ricardo, S.; Ponte, F.; Costa, A.; Lopes, J.M.; David, L. Peritoneal dissemination of ovarian cancer: Role of MUC16-mesothelin interaction and implications for treatment. Expert Rev. Anticancer Ther. 2018, 18, 177–186. [Google Scholar] [CrossRef]
- Chang, K.; Pai, L.H.; Batra, J.K.; Pastan, I.; Willingham, M.C. Characterization of the antigen (CAK1) recognized by monoclonal antibody K1 present on ovarian cancers and normal mesothelium. Cancer Res. 1992, 52, 181–186. [Google Scholar]
- Tchou, J.; Wang, L.-C.; Selven, B.; Zhang, H.; Conejo-Garcia, J.; Borghaei, H.; Kalos, M.; Vondeheide, R.H.; Albelda, S.M.; June, C.H.; et al. Mesothelin, a novel immunotherapy target for triple negative breast cancer. Breast Cancer Res. Treat. 2012, 133, 799–804. [Google Scholar] [CrossRef] [Green Version]
- Tozbikian, G.; Brogi, E.; Kadota, K.; Catalano, J.; Akram, M.; Patil, S.; Ho, A.Y.; Reis-Filho, J.S.; Weigelt, B.; Norton, L.; et al. Mesothelin Expression in Triple Negative Breast Carcinomas Correlates Significantly with Basal-Like Phenotype, Distant Metastases and Decreased Survival. PLoS ONE 2014, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thomas, A. Should anti-mesothelin therapies be explored in lung cancer? Expert Rev. Anticancer Ther. 2016, 16, 677–679. [Google Scholar] [CrossRef] [PubMed]
- Le, K.; Wang, J.; Zhang, T.; Guo, Y.; Chang, H.; Wang, S.; Zhu, B. Overexpression of Mesothelin in Pancreatic Ductal Adenocarcinoma (PDAC). Int. J. Med. Sci. 2020, 17, 422–427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sahni, S.; Moon, E.A.; Howell, V.M.; Mehta, S.; Pavlakis, N.; Chan, D.; Ahadi, M.S.; Gill, A.J.; Samra, J.; Mittal, A. Tissue biomarker panel as a surrogate marker for squamous subtype of pancreatic cancer. Eur. J Surg. Oncol. 2020. [Google Scholar] [CrossRef]
- Nahm, C.B.; Turchini, J.; Jamieson, N.; Moon, E.; Sioson, L.; Itchins, M.; Arena, J.; Colvin, E.; Howell, V.M.; Pavlakis, N.; et al. Biomarker panel predicts survival after resection in pancreatic ductal adenocarcinoma: A multi-institutional cohort study. Eur. J. Surg. Oncol. 2019, 45, 218–224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sopha, S.C.; Gopal, P.; Merchant, N.B.; Revetta, F.L.; Gold, D.V.; Washington, K.; Shi, C. Diagnostic and therapeutic implications of a novel immunohistochemical panel detecting duodenal mucosal invasion by pancreatic ductal adenocarcinoma. Int. J. Clin. Exp. Pathol. 2013, 6, 2476–2486. [Google Scholar]
- Montemagno, C.; Cassim, S.; Trichanh, D.; Savary, C.; Pouyssegur, J.; Pagès, G.; Fagret, D.; Broisat, A.; Ghezzi, C. 99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma. Cancers 2019, 11, 1531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, M.; Bharadwaj, U.; Zhang, R.; Zhang, S.; Mu, H.; Fisher, W.E.; Brunicardi, F.C.; Chen, C.; Yao, Q. Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer. Mol. Cancer Ther. 2008, 7, 286–296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bharadwaj, U.; Li, M.; Chen, C.; Yao, Q. Mesothelin-induced pancreatic cancer cell proliferation involves alteration of cyclin E via activation of signal transducer and activator of transcription protein 3. Mol. Cancer Res. 2008, 6, 1755–1765. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bharadwaj, U.; Marin-Muller, C.; Li, M.; Chen, C.; Yao, Q. Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation. Carcinogenesis 2011, 32, 1013–1024. [Google Scholar] [CrossRef] [Green Version]
- Wang, K.; Bodempudi, V.; Liu, Z.; Borrego-Diaz, E.; Yamoutpoor, F.; Meyer, A.; Woo, R.A.; Pan, W.; Dudek, A.Z.; Olyaee, M.S.; et al. Inhibition of Mesothelin as a Novel Strategy for Targeting Cancer Cells. PLoS ONE 2012, 7. [Google Scholar] [CrossRef]
- Bharadwaj, U.; Marin-Muller, C.; Li, M.; Chen, C.; Yao, Q. Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression. Mol. Cancer 2011, 10, 106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zheng, C.; Jia, W.; Tang, Y.; Zhao, H.; Jiang, Y.; Sun, S. Mesothelin regulates growth and apoptosis in pancreatic cancer cells through p53-dependent and -independent signal pathway. J. Exp. Clin. Cancer Res. 2012, 31, 84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Uehara, N.; Matsuoka, Y.; Tsubura, A. Mesothelin promotes anchorage-independent growth and prevents anoikis via extracellular signal-regulated kinase signaling pathway in human breast cancer cells. Mol. Cancer Res. 2008, 6, 186–193. [Google Scholar] [CrossRef] [Green Version]
- Golfier, S.; Kopitz, C.; Kahnert, A.; Heisler, I.; Schatz, C.A.; Stelte-Ludwig, B.; Mayer-Bartschmid, A.; Unterschemmann, K.; Bruder, S.; Linden, L.; et al. Anetumab ravtansine: A novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol. Cancer Ther. 2014, 13, 1537–1548. [Google Scholar] [CrossRef] [Green Version]
- Shimizu, A.; Hirono, S.; Tani, M.; Kawai, M.; Okada, K.-I.; Miyazawa, M.; Kitahata, Y.; Nakamura, Y.; Noda, T.; Yokoyama, S.; et al. Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma. Cancer Sci. 2012, 103, 739–746. [Google Scholar] [CrossRef]
- Chen, S.-H.; Hung, W.-C.; Wang, P.; Paul, C.; Konstantopoulos, K. Mesothelin Binding to CA125/MUC16 Promotes Pancreatic Cancer Cell Motility and Invasion via MMP-7 Activation. Sci. Rep. 2013, 3, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 2009, 119, 1420–1428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mittal, V. Epithelial Mesenchymal Transition in Tumor Metastasis. Annu. Rev. Pathol. 2018, 13, 395–412. [Google Scholar] [CrossRef] [PubMed]
- He, X.; Wang, L.; Riedel, H.; Wang, K.; Yang, Y.; Dinu, C.Z.; Rojanasakul, Y. Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. Mol. Cancer 2017, 16. [Google Scholar] [CrossRef] [Green Version]
- Avula, L.R.; Rudloff, M.; El-Behaedi, S.; Arons, D.; Albalawy, R.; Chen, X.; Zhang, X.; Alewine, C. Mesothelin enhances tumor vascularity in newly forming pancreatic peritoneal metastases. Mol. Cancer Res. 2019. [Google Scholar] [CrossRef] [Green Version]
- Melaiu, O.; Stebbing, J.; Lombardo, Y.; Bracci, E.; Uehara, N.; Bonotti, A.; Cristaudo, A.; Foddis, R.; Mutti, L.; Barale, R.; et al. MSLN Gene Silencing Has an Anti-Malignant Effect on Cell Lines Overexpressing Mesothelin Deriving from Malignant Pleural Mesothelioma. PLoS ONE 2014, 9, e85935. [Google Scholar] [CrossRef] [Green Version]
- Cheng, W.-F.; Huang, C.-Y.; Chang, M.-C.; Hu, Y.-H.; Chiang, Y.-C.; Chen, Y.-L.; Hsieh, C.-Y.; Chen, C.-A. High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. Br. J. Cancer 2009, 100, 1144–1153. [Google Scholar] [CrossRef] [Green Version]
- Ren, Y.R.; Patel, K.; Paun, B.C.; Kern, S.E. Structural Analysis of the Cancer-specific Promoter in Mesothelin and in Other Genes Overexpressed in Cancers. J. Biol. Chem. 2011, 286, 11960–11969. [Google Scholar] [CrossRef] [Green Version]
- De Santi, C.; Vencken, S.; Blake, J.; Haase, B.; Benes, V.; Gemignani, F.; Landi, S.; Greene, C.M. Identification of MiR-21-5p as a Functional Regulator of Mesothelin Expression Using MicroRNA Capture Affinity Coupled with Next Generation Sequencing. PLoS ONE 2017, 12, e0170999. [Google Scholar] [CrossRef] [PubMed]
- Marin-Muller, C.; Li, D.; Bharadwaj, U.; Li, M.; Chen, C.; Hodges, S.E.; Fisher, W.E.; Mo, Q.; Hung, M.-C.; Yao, Q. A Tumorigenic Factor Interactome Connected Through Tumor Suppressor MicroRNA-198 in Human Pancreatic Cancer. Clin. Cancer Res. 2013, 19, 5901–5913. [Google Scholar] [CrossRef] [Green Version]
- Wu, X.; Li, D.; Liu, L.; Liu, B.; Liang, H.; Yang, B. Serum soluble mesothelin-related peptide (SMRP): A potential diagnostic and monitoring marker for epithelial ovarian cancer. Arch. Gynecol. Obs. 2014, 289, 1309–1314. [Google Scholar] [CrossRef]
- Robinson, B.W.S.; Creaney, J.; Lake, R.; Nowak, A.; Musk, A.W.; de Klerk, N.; Winzell, P.; Hellstrom, K.E.; Hellstrom, I. Soluble mesothelin-related protein—A blood test for mesothelioma. Lung Cancer 2005, 49 (Suppl. 1), S109–S111. [Google Scholar] [CrossRef] [PubMed]
- Beyer, H.L.; Geschwindt, R.D.; Glover, C.L.; Tran, L.; Hellstrom, I.; Hellstrom, K.-E.; Miller, M.C.; Verch, T.; Allard, W.J.; Pass, H.I.; et al. MESOMARK: A potential test for malignant pleural mesothelioma. Clin. Chem. 2007, 53, 666–672. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sharon, E.; Zhang, J.; Hollevoet, K.; Steinberg, S.M.; Pastan, I.; Onda, M.; Gaedcke, J.; Ghadimi, B.M.; Ried, T.; Hassan, R. Serum mesothelin and megakaryocyte potentiating factor in pancreatic and biliary cancers. Clin. Chem. Lab. Med. 2012, 50, 721–725. [Google Scholar] [CrossRef] [PubMed]
- Hassan, R.; Wu, C.; Brechbiel, M.W.; Margulies, I.; Kreitman, R.J.; Pastan, I. 111Indium-labeled monoclonal antibody K1: Biodistribution study in nude mice bearing a human carcinoma xenograft expressing mesothelin. Int. J. Cancer 1999, 80, 559–563. [Google Scholar] [CrossRef]
- Kobayashi, K.; Sasaki, T.; Takenaka, F.; Yakushiji, H.; Fujii, Y.; Kishi, Y.; Kita, S.; Shen, L.; Kumon, H.; Matsuura, E. A Novel PET Imaging Using 64Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells. J. Immunol. Res. 2015, 2015. [Google Scholar] [CrossRef] [Green Version]
- Ter Weele, E.J.; Terwisscha van Scheltinga, A.G.T.; Kosterink, J.G.W.; Pot, L.; Vedelaar, S.R.; Lamberts, L.E.; Williams, S.P.; Lub-de Hooge, M.N.; de Vries, E.G.E. Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with 89Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts. Oncotarget 2015, 6, 42081–42090. [Google Scholar] [CrossRef] [Green Version]
- Van Scheltinga, A.G.T.T.; Ogasawara, A.; Pacheco, G.; Vanderbilt, A.N.; Tinianow, J.N.; Gupta, N.; Li, D.; Firestein, R.; Marik, J.; Scales, S.J.; et al. Preclinical Efficacy of an Antibody–Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET. Mol. Cancer Ther. 2017, 16, 134–142. [Google Scholar] [CrossRef] [Green Version]
- Lamberts, L.E.; Menke-van der Houven van Oordt, C.W.; ter Weele, E.J.; Bensch, F.; Smeenk, M.M.; Voortman, J.; Hoekstra, O.S.; Williams, S.P.; Fine, B.M.; Maslyar, D.; et al. ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody-Drug Conjugate Treatment. Clin. Cancer Res. 2016, 22, 1642–1652. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lindenberg, L.; Thomas, A.; Adler, S.; Mena, E.; Kurdziel, K.; Maltzman, J.; Wallin, B.; Hoffman, K.; Pastan, I.; Paik, C.H.; et al. Safety and biodistribution of 111In-amatuximab in patients with mesothelin expressing cancers using single photon emission computed tomography-computed tomography (SPECT-CT) imaging. Oncotarget 2015, 6, 4496–4504. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yakushiji, H.; Kobayashi, K.; Takenaka, F.; Kishi, Y.; Shinohara, M.; Akehi, M.; Sasaki, T.; Ohno, E.; Matsuura, E. Novel single-chain variant of antibody against mesothelin established by phage library. Cancer Sci. 2019, 110, 2722–2733. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ho, M.; Hassan, R.; Zhang, J.; Wang, Q.-C.; Onda, M.; Bera, T.; Pastan, I. Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients. Clin. Cancer Res. 2005, 11, 3814–3820. [Google Scholar] [CrossRef] [Green Version]
- Pastan, I.; Hassan, R.; Fitzgerald, D.J.; Kreitman, R.J. Immunotoxin therapy of cancer. Nat. Rev. Cancer 2006, 6, 559–565. [Google Scholar] [CrossRef] [PubMed]
- Hassan, R.; Williams-Gould, J.; Steinberg, S.M.; Liewehr, D.J.; Yokokawa, J.; Tsang, K.Y.; Surawski, R.J.; Scott, T.; Camphausen, K. Tumor-directed radiation and the immunotoxin SS1P in the treatment of mesothelin-expressing tumor xenografts. Clin. Cancer Res. 2006, 12, 4983–4988. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mossoba, M.E.; Onda, M.; Taylor, J.; Massey, P.R.; Treadwell, S.; Sharon, E.; Hassan, R.; Pastan, I.; Fowler, D.H. Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts. Clin. Cancer Res. 2011, 17, 3697–3705. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hassan, R.; Bullock, S.; Premkumar, A.; Kreitman, R.J.; Kindler, H.; Willingham, M.C.; Pastan, I. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin. Cancer Res. 2007, 13, 5144–5149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hassan, R.; Sharon, E.; Thomas, A.; Zhang, J.; Ling, A.; Miettinen, M.; Kreitman, R.J.; Steinberg, S.M.; Hollevoet, K.; Pastan, I. Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125. Cancer 2014, 120, 3311–3319. [Google Scholar] [CrossRef]
- Hassan, R.; Miller, A.C.; Sharon, E.; Thomas, A.; Reynolds, J.C.; Ling, A.; Kreitman, R.J.; Miettinen, M.M.; Steinberg, S.M.; Fowler, D.H.; et al. Major Cancer Regressions in Mesothelioma After Treatment with an Anti-Mesothelin Immunotoxin and Immune Suppression. Sci. Transl. Med. 2013, 5, 208ra147. [Google Scholar] [CrossRef]
- Hollevoet, K.; Mason-Osann, E.; Liu, X.; Imhof-Jung, S.; Niederfellner, G.; Pastan, I. In vitro and in vivo activity of the low-immunogenic antimesothelin immunotoxin RG7787 in pancreatic cancer. Mol. Cancer Ther. 2014, 13, 2040–2049. [Google Scholar] [CrossRef] [Green Version]
- Zhang, J.; Khanna, S.; Jiang, Q.; Alewine, C.; Miettinen, M.; Pastan, I.; Hassan, R. Efficacy of Anti-mesothelin Immunotoxin RG7787 plus Nab-Paclitaxel against Mesothelioma Patient-Derived Xenografts and Mesothelin as a Biomarker of Tumor Response. Clin. Cancer Res. 2017, 23, 1564–1574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kolyvas, E.; Rudloff, M.; Poruchynsky, M.; Landsman, R.; Hollevoet, K.; Venzon, D.; Alewine, C. Mesothelin-targeted immunotoxin RG7787 has synergistic anti-tumor activity when combined with taxanes. Oncotarget 2017, 8, 9189–9199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, X.-F.; Zhou, Q.; Hassan, R.; Pastan, I. Panbinostat decreases cFLIP and enhances killing of cancer cells by immunotoxin LMB-100 by stimulating the extrinsic apoptotic pathway. Oncotarget 2017, 8, 87307–87316. [Google Scholar] [CrossRef] [Green Version]
- Hassan, R.; Ebel, W.; Routhier, E.L.; Patel, R.; Kline, J.B.; Zhang, J.; Chao, Q.; Jacob, S.; Turchin, H.; Gibbs, L.; et al. Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. Cancer Immun. 2007, 7, 20. [Google Scholar]
- Mizukami, T.; Kamachi, H.; Fujii, Y.; Matsuzawa, F.; Einama, T.; Kawamata, F.; Kobayashi, N.; Hatanaka, Y.; Taketomi, A. 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. [Google Scholar] [CrossRef] [Green Version]
- Hassan, R.; Cohen, S.J.; Phillips, M.; Pastan, I.; Sharon, E.; Kelly, R.J.; Schweizer, C.; Weil, S.; Laheru, D. Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin. Cancer Res. 2010, 16, 6132–6138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hassan, R.; Kindler, H.L.; Jahan, T.; Bazhenova, L.; Reck, M.; Thomas, A.; Pastan, I.; Parno, J.; O’Shannessy, D.J.; Fatato, P.; et al. Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin. Cancer Res. 2014, 20, 5927–5936. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gupta, A.; Hussein, Z.; Hassan, R.; Wustner, J.; Maltzman, J.D.; Wallin, B.A. Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection. Cancer Chemother. Pharmacol. 2016, 77, 733–743. [Google Scholar] [CrossRef]
- Hassan, R.; Blumenschein, G.R.; Moore, K.N.; Santin, A.D.; Kindler, H.L.; Nemunaitis, J.J.; Seward, S.M.; Thomas, A.; Kim, S.K.; Rajagopalan, P.; et al. First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors. J. Clin. Oncol. 2020, JCO1902085. [Google Scholar] [CrossRef]
- Scales, S.J.; Gupta, N.; Pacheco, G.; Firestein, R.; French, D.M.; Koeppen, H.; Rangell, L.; Barry-Hamilton, V.; Luis, E.; Chuh, J.; et al. An antimesothelin-monomethyl auristatin e conjugate with potent antitumor activity in ovarian, pancreatic, and mesothelioma models. Mol. Cancer Ther. 2014, 13, 2630–2640. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Weekes, C.D.; Lamberts, L.E.; Borad, M.J.; Voortman, J.; McWilliams, R.R.; Diamond, J.R.; de Vries, E.G.E.; Verheul, H.M.; Lieu, C.H.; Kim, G.P.; et al. Phase I Study of DMOT4039A, an Antibody-Drug Conjugate Targeting Mesothelin, in Patients with Unresectable Pancreatic or Platinum-Resistant Ovarian Cancer. Mol. Cancer Ther. 2016, 15, 439–447. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, X.-Y.; Subramanyam, B.; Sarapa, N.; Golfier, S.; Dinter, H. Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors. Clin. Cancer Drugs 2016, 3, 76–86. [Google Scholar] [CrossRef]
- Clarke, J.; Chu, S.-C.; Siu, L.L.; Machiels, J.-P.; Markman, B.; Heinhuis, K.; Millward, M.; Lolkema, M.; Patel, S.P.; de Souza, P.; et al. Abstract B057: BMS-986148, an anti-mesothelin antibody-drug conjugate (ADC), alone or in combination with nivolumab demonstrates clinical activity in patients with select advanced solid tumors. Mol. Cancer Ther. 2019, 18, B057. [Google Scholar] [CrossRef]
- Targeted Alpha Therapy Working Group; Parker, C.; Lewington, V.; Shore, N.; Kratochwil, C.; Levy, M.; Lindén, O.; Noordzij, W.; Park, J.; Saad, F. Targeted Alpha Therapy, an Emerging Class of Cancer Agents: A Review. JAMA Oncol. 2018, 4, 1765–1772. [Google Scholar] [CrossRef] [PubMed]
- Wickstroem, K.; Hagemann, U.B.; Cruciani, V.; Wengner, A.M.; Kristian, A.; Ellingsen, C.; Siemeister, G.; Bjerke, R.M.; Karlsson, J.; Ryan, O.B.; et al. Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models. J. Nucl. Med. 2019, 60, 1293–1300. [Google Scholar] [CrossRef] [Green Version]
- Laheru, D.; Lutz, E.; Burke, J.; Biedrzycki, B.; Solt, S.; Onners, B.; Tartakovsky, I.; Nemunaitis, J.; Le, D.; Sugar, E.; et al. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: A pilot study of safety, feasibility, and immune activation. Clin. Cancer Res. 2008, 14, 1455–1463. [Google Scholar] [CrossRef] [Green Version]
- Lutz, E.; Yeo, C.J.; Lillemoe, K.D.; Biedrzycki, B.; Kobrin, B.; Herman, J.; Sugar, E.; Piantadosi, S.; Cameron, J.L.; Solt, S.; et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann. Surg. 2011, 253, 328–335. [Google Scholar] [CrossRef] [Green Version]
- Le, D.T.; Brockstedt, D.G.; Nir-Paz, R.; Hampl, J.; Mathur, S.; Nemunaitis, J.; Sterman, D.H.; Hassan, R.; Lutz, E.; Moyer, B.; et al. A Live-attenuated Listeria Vaccine (ANZ-100) and a Live-attenuated Listeria Vaccine Expressing Mesothelin (CRS-207) for Advanced Cancers: Phase 1 Studies of Safety and Immune Induction. Clin. Cancer Res. 2012, 18, 858–868. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Le, D.T.; Picozzi, V.J.; Ko, A.H.; Wainberg, Z.A.; Kindler, H.; Wang-Gillam, A.; Oberstein, P.; Morse, M.A.; Zeh, H.J.; Weekes, C.; et al. Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study). Clin. Cancer Res. 2019, 25, 5493–5502. [Google Scholar] [CrossRef] [PubMed]
- Chang, M.-C.; Chen, Y.-L.; Chiang, Y.-C.; Chen, T.-C.; Tang, Y.-C.; Chen, C.-A.; Sun, W.-Z.; Cheng, W.-F. Mesothelin-specific cell-based vaccine generates antigen-specific immunity and potent antitumor effects by combining with IL-12 immunomodulator. Gene Ther. 2016, 23, 38–49. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nomi, T.; Sho, M.; Akahori, T.; Hamada, K.; Kubo, A.; Kanehiro, H.; Nakamura, S.; Enomoto, K.; Yagita, H.; Azuma, M.; et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 2007, 13, 2151–2157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Soares, K.C.; Rucki, A.A.; Wu, A.A.; Olino, K.; Xiao, Q.; Chai, Y.; Wamwea, A.; Bigelow, E.; Lutz, E.; Liu, L.; et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J. Immunother. 2015, 38, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tsujikawa, T.; Crocenzi, T.; Durham, J.N.; Sugar, E.A.; Wu, A.A.; Onners, B.; Nauroth, J.M.; Anders, R.A.; Fertig, E.J.; Laheru, D.A.; et al. Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-mesothelin (CRS-207) With or Without Nivolumab in Patients with Pancreatic Cancer. Clin. Cancer Res. 2020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jackson, H.J.; Rafiq, S.; Brentjens, R.J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 2016, 13, 370–383. [Google Scholar] [CrossRef]
- Qin, L.; Zhao, R.; Li, P. Incorporation of functional elements enhances the antitumor capacity of CAR T cells. Exp. Hematol. Oncol. 2017, 6. [Google Scholar] [CrossRef]
- Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D.; et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 439–448. [Google Scholar] [CrossRef]
- Stromnes, I.M.; Schmitt, T.M.; Hulbert, A.; Brockenbrough, J.S.; Nguyen, H.; Cuevas, C.; Dotson, A.M.; Tan, X.; Hotes, J.L.; Greenberg, P.D.; et al. T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma. Cancer Cell 2015, 28, 638–652. [Google Scholar] [CrossRef] [Green Version]
- He, J.; Zhang, Z.; Lv, S.; Liu, X.; Cui, L.; Jiang, D.; Zhang, Q.; Li, L.; Qin, W.; Jin, H.; et al. Engineered CAR T cells targeting mesothelin by piggyBac transposon system for the treatment of pancreatic cancer. Cell. Immunol. 2018, 329, 31–40. [Google Scholar] [CrossRef]
- Sun, Q.; Zhou, S.; Zhao, J.; Deng, C.; Teng, R.; Zhao, Y.; Chen, J.; Dong, J.; Yin, M.; Bai, Y.; et al. Engineered T lymphocytes eliminate lung metastases in models of pancreatic cancer. Oncotarget 2018, 9, 13694–13705. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Adusumilli, P.S.; Cherkassky, L.; Villena-Vargas, J.; Colovos, C.; Servais, E.; Plotkin, J.; Jones, D.R.; Sadelain, M. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 2014, 6, 261ra151. [Google Scholar] [CrossRef] [Green Version]
- Lv, J.; Zhao, R.; Wu, D.; Zheng, D.; Wu, Z.; Shi, J.; Wei, X.; Wu, Q.; Long, Y.; Lin, S.; et al. Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer. J. Hematol. Oncol. 2019, 12, 18. [Google Scholar] [CrossRef] [Green Version]
- Beatty, G.L.; O’Hara, M.H.; Lacey, S.F.; Torigian, D.A.; Nazimuddin, F.; Chen, F.; Kulikovskaya, I.M.; Soulen, M.C.; McGarvey, M.; Nelson, A.M.; et al. Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. Gastroenterology 2018, 155, 29–32. [Google Scholar] [CrossRef] [PubMed]
- Morello, A.; Sadelain, M.; Adusumilli, P.S. Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discov. 2016, 6, 133–146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Agent | Title | Status | Phase | NCT/References |
---|---|---|---|---|
SS1P | Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. | Completed (Results available) | I | [78] |
LMB-100/RG7787 | Mesothelin-targeted immunotoxin LMB-100 alone or in combination with Nab-Paclitaxel in people with previously treated metastatic and/or locally advanced PDAC and mesothelin-expressing solid tumors. | Active | I/II | NCT02810418 |
Mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in persons with previously treated metastatic PDAC and other mesothelin-expressing solid tumors. | Recruiting | I | NCT04034238 | |
Amatuximab | Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. | Completed (Results available) | I | [87] |
Anetumab ravtansine | First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors. | Completed (Results available) | Ib | [90] |
Phase II anetumab ravtansine in pre-treated mesothelin-expressing pancreatic cancer | Completed | II | NCT03023722 | |
DMOT4039A | Phase I study of DMOT4039A, an antibody-drug conjugate targeting mesothelin, in patients with unresectable pancreatic or platinum-resistant ovarian cancer. | Completed (Results available) | I | [92] |
BMS-986148 | A study of BMS-986148 in patients with selected advanced solid tumors. | Completed | I/II | NCT02341625 |
BAY2287411 | First in human study of BAY2287411 injection, a Thorium-227 labeled antibody-chelator conjugate, in patients with tumors known to express mesothelin. | Recruiting | I | NCT03507452 |
CRS-207 | A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. | Completed (Results available) | I | [99] |
Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study). | Completed (Results available) | IIb | [100] | |
Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-mesothelin (CRS-207) With or Without Nivolumab in Patients with Pancreatic Cancer. | Completed (Results available) | II | [105] | |
CAR-T cells | Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. | Completed (Results available) | I | [114] |
CAR T Cell immunotherapy for pancreatic cancer. | Active | I | NCT03323944 | |
A study of mesothelin redirected autologous T cells for advanced pancreatic carcinoma. | Unknown | I | NCT02706782 | |
Evaluate the safety and efficacy of CAR-T in the treatment of pancreatic cancer. | Unknown | I | NCT03267173 | |
PD-1 antibody expressing mesoCAR-T cells for mesothelin positive advanced solid tumor. | Recruiting | I/II | NCT03615313 | |
CTLA-4 and PD-1 antibodies expressing mesothelin-CAR-T cells for mesothelin positive advanced solid tumor. | Unknown | I/II | NCT03182803 | |
Study of PD-1 gene-knocked out mesothelin-directed CAR-T cells with the conditioning of PC in mesothelin positive multiple solid tumors. | Recruiting | I | NCT03747965 |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Montemagno, C.; Cassim, S.; Pouyssegur, J.; Broisat, A.; Pagès, G. From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci. 2020, 21, 4067. https://doi.org/10.3390/ijms21114067
Montemagno C, Cassim S, Pouyssegur J, Broisat A, Pagès G. From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma. International Journal of Molecular Sciences. 2020; 21(11):4067. https://doi.org/10.3390/ijms21114067
Chicago/Turabian StyleMontemagno, Christopher, Shamir Cassim, Jacques Pouyssegur, Alexis Broisat, and Gilles Pagès. 2020. "From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma" International Journal of Molecular Sciences 21, no. 11: 4067. https://doi.org/10.3390/ijms21114067