Mesothelin-targeted Agents in Clinical Trials and in Preclinical Development

Overview

Journal Mol Cancer Ther

Date 2012 Feb 22

PMID 22351743

Citations 63

Authors

Ronan J Kelly

Elad Sharon

Ira Pastan

Raffit Hassan

Affiliations

Soon will be listed here.

Abstract

Mesothelin is a tumor differentiation antigen that is highly expressed in several malignant diseases in humans, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissues and its high expression in many common cancers make it an attractive candidate for cancer therapy. Several agents, including an immunotoxin, monoclonal antibody, antibody drug conjugate, and tumor vaccine, are in various stages of development to treat patients with mesothelin-expressing tumors. This review highlights ongoing clinical trials, as well as other approaches to exploit mesothelin for cancer therapy, that are in preclinical development.

Citing Articles

Characterization of mesothelin gene expression in dogs and overexpression in canine mesotheliomas.

Nabeta R, Kanaya A, Shimada K, Matsuura K, Yoshimura A, Oyamada T Front Vet Sci. 2024; 11:1436621.

PMID: 39315086 PMC: 11417096. DOI: 10.3389/fvets.2024.1436621.

Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia.

Jang Y, Koh J, Park J, Choi S, Duong P, Heo B Int J Mol Sci. 2024; 25(4).

PMID: 38396817 PMC: 10888725. DOI: 10.3390/ijms25042140.

Mesothelin expression in gynecologic carcinosarcoma: clinicopathological significance and correlation with HER2 expression.

Kitadai R, Nishikawa T, Yoshida H, Mizoguchi C, Yamamoto K, Kato T J Gynecol Oncol. 2023; 35(2):e11.

PMID: 37914528 PMC: 10948979. DOI: 10.3802/jgo.2024.35.e11.

Biology of Mesothelin and Clinical Implications: A Review of Existing Literature.

Hagerty B, Takabe K World J Oncol. 2023; 14(5):340-349.

PMID: 37869242 PMC: 10588497. DOI: 10.14740/wjon1655.

Improvements in Systemic Therapies for Advanced Malignant Mesothelioma.

Deiana C, Fabbri F, Tavolari S, Palloni A, Brandi G Int J Mol Sci. 2023; 24(13).

PMID: 37445594 PMC: 10342038. DOI: 10.3390/ijms241310415.

References

Brockstedt D, Giedlin M, Leong M, Bahjat K, Gao Y, Luckett W . Listeria-based cancer vaccines that segregate immunogenicity from toxicity. Proc Natl Acad Sci U S A. 2004; 101(38):13832-7. PMC: 518841. DOI: 10.1073/pnas.0406035101. View

Chowdhury P, Viner J, Beers R, Pastan I . Isolation of a high-affinity stable single-chain Fv specific for mesothelin from DNA-immunized mice by phage display and construction of a recombinant immunotoxin with anti-tumor activity. Proc Natl Acad Sci U S A. 1998; 95(2):669-74. PMC: 18478. DOI: 10.1073/pnas.95.2.669. View

Miettinen M, Sarlomo-Rikala M . Expression of calretinin, thrombomodulin, keratin 5, and mesothelin in lung carcinomas of different types: an immunohistochemical analysis of 596 tumors in comparison with epithelioid mesotheliomas of the pleura. Am J Surg Pathol. 2003; 27(2):150-8. DOI: 10.1097/00000478-200302000-00002. View

Hassan R, Schweizer C, Lu K, Schuler B, Remaley A, Weil S . Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy. Lung Cancer. 2009; 68(3):455-9. PMC: 2864325. DOI: 10.1016/j.lungcan.2009.07.016. View

Li Q, Verschraegen C, Mendoza J, Hassan R . Cytotoxic activity of the recombinant anti-mesothelin immunotoxin, SS1(dsFv)PE38, towards tumor cell lines established from ascites of patients with peritoneal mesotheliomas. Anticancer Res. 2004; 24(3a):1327-35. View

Till B, Jensen M, Wang J, Chen E, Wood B, Greisman H . Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008; 112(6):2261-71. PMC: 2532803. DOI: 10.1182/blood-2007-12-128843. View

Hassan R, Bera T, Pastan I . Mesothelin: a new target for immunotherapy. Clin Cancer Res. 2004; 10(12 Pt 1):3937-42. DOI: 10.1158/1078-0432.CCR-03-0801. View

Rump A, Morikawa Y, Tanaka M, Minami S, Umesaki N, Takeuchi M . Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J Biol Chem. 2003; 279(10):9190-8. DOI: 10.1074/jbc.M312372200. View

Hassan R, Bullock S, Premkumar A, Kreitman R, Kindler H, Willingham M . 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(17):5144-9. DOI: 10.1158/1078-0432.CCR-07-0869. View

10.

Hassan R, Kreitman R, Pastan I, Willingham M . Localization of mesothelin in epithelial ovarian cancer. Appl Immunohistochem Mol Morphol. 2005; 13(3):243-7. DOI: 10.1097/01.pai.00000141545.36485.d6. View

11.

Argani P, Iacobuzio-Donahue C, Ryu B, Rosty C, Goggins M, Wilentz R . Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001; 7(12):3862-8. View

12.

Yamaguchi N, Hattori K, Kojima T, Imai N, Ochi N . A novel cytokine exhibiting megakaryocyte potentiating activity from a human pancreatic tumor cell line HPC-Y5. J Biol Chem. 1994; 269(2):805-8. View

13.

Ordonez N . Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol. 2003; 27(11):1418-28. DOI: 10.1097/00000478-200311000-00003. View

14.

Thomas A, Santarsiero L, Lutz E, Armstrong T, Chen Y, Huang L . Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med. 2004; 200(3):297-306. PMC: 2211979. DOI: 10.1084/jem.20031435. View

15.

Zhang Y, Xiang L, Hassan R, Pastan I . Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors. Proc Natl Acad Sci U S A. 2007; 104(43):17099-104. PMC: 2040446. DOI: 10.1073/pnas.0708101104. View

16.

Gubbels J, Belisle J, Onda M, Rancourt C, Migneault M, Ho M . Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol Cancer. 2006; 5(1):50. PMC: 1635730. DOI: 10.1186/1476-4598-5-50. View

17.

Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B . 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(5):1455-63. PMC: 2879140. DOI: 10.1158/1078-0432.CCR-07-0371. View

18.

Chowdhury P, Pastan I . Improving antibody affinity by mimicking somatic hypermutation in vitro. Nat Biotechnol. 1999; 17(6):568-72. DOI: 10.1038/9872. View

19.

Hassan R, Ho M . Mesothelin targeted cancer immunotherapy. Eur J Cancer. 2007; 44(1):46-53. PMC: 2265108. DOI: 10.1016/j.ejca.2007.08.028. View

20.

Carpenito C, Milone M, Hassan R, Simonet J, Lakhal M, Suhoski M . Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009; 106(9):3360-5. PMC: 2651342. DOI: 10.1073/pnas.0813101106. View