Mesothelin as a target for cervical cancer therapy

Our plain-English summary of Mesothelin as a target for cervical cancer therapy, by K. Jöhrens, L. Lazzerini, J. Barinoff, et al (Archives of Gynecology and Obstetrics, 2019).

The study

• Authors: K. Jöhrens, L. Lazzerini, J. Barinoff, J. Sehouli, G. Cichon
• Journal: Archives of Gynecology and Obstetrics
• Published: 2019;299(1):211-216
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: The cell surface glycoprotein Mesothelin is overexpressed in several tumor entities and novel immune-based therapies are currently under the early clinical evaluation for the treatment of malignant pleura mesothelioma, ovarian cancer, and pancreatic cancer. Cervical cancer has not been recognized as a suitable target for Mesothelin-directed immune therapies so far.

Methods: To exploit a possible role of Mesothelin in cervical cancer treatment, we analysed Mesothelin expression in 79 cervical carcinomas and aligned expressions patterns with tumor growth parameters. A novel anti-Mesothelin drug conjugate (Anetumab Ravtansine) was applied for dose-efficiency studies in a Mesothelin positive tumor model for cervical cancer in Scid mice.

Results: In more than three-quarters (77%) of cervical adenocarcinomas, Mesothelin was expressed to high levels. Among squamous cell carcinomas of the cervix uteri expression levels were lower and expression patterns were less intense, but still ranged between 50-60% (57%). A significant correlation between Mesothelin expression levels and tumor grade, metastatic behaviour, and lymph- or hemangiosis was not found. The novel anti-Mesothelin-drug conjugate (Anetumab Ravtansine) showed a substantial dose-dependent therapeutic efficiency in a xenotransplant model for cervical cancer in SCID mice (hela cell tumors). Applying the ADC at a dose of 10 mg/kg twice weekly induced complete tumor regression in 88% of animals within 6 weeks.

Conclusions: Mesothelin should be taken into account as a target in cervical cancer therapy and histological determination of Mesothelin expression should be considered in routine diagnostics of cervical carcinomas.

In plain English

This laboratory study did not concern asbestos. It examined mesothelin, a cell-surface protein, as a possible drug target in cervical cancer. The authors stained archived tissue from 79 cervical cancers diagnosed between 2006 and 2015 at the Charité in Berlin: 53 squamous cell carcinomas and 26 adenocarcinomas. Overall, 50 of 79 (63%) were positive for mesothelin. High levels were found in 19 of 26 adenocarcinomas (73%). Among squamous cell carcinomas, 30 of 53 (57%) were positive, with weaker staining. Mesothelin levels showed no significant correlation with lymph node status, tumor grade or invasion of blood and lymph vessels. In mice carrying tumors grown from HeLa human cervical cancer cells, the anti-mesothelin drug anetumab ravtansine, given twice weekly, worked in a dose-dependent way. At 2 mg/kg it slowed tumor growth. At 5 mg/kg it healed 2 of 8 mice. At 10 mg/kg the cure rate was 88% (7 of 8). The authors noted that the drug does not bind mouse mesothelin, so side effects in the mice were limited. They concluded that cervical adenocarcinomas are favoured as a target for mesothelin-directed therapies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory study: immunohistochemical staining of archived tumor tissue, plus an animal experiment (human tumor xenografts in mice)
• Who was studied: Archived tissue from 53 squamous cell carcinomas and 26 adenocarcinomas of the cervix, Charité department of pathology, Berlin, first diagnosed 2006 to 2015, with pre-treated cases excluded. Also SCID-beige mice with HeLa cell tumors, in four groups of 5 to 8 animals.
• Exposure: No asbestos exposure was studied. In the mouse experiment, the anti-mesothelin drug conjugate anetumab ravtansine was given at 2, 5 or 10 mg/kg twice weekly by injection into the abdomen. Control mice received injection buffer only.
• Main results:
  • 50 of 79 (63%) of all cervical carcinomas were positive for mesothelin.
  • Among adenocarcinomas, 19 of 26 (73%) showed high mesothelin levels and 6 of 26 (23%) showed none.
  • Among squamous cell carcinomas, 30 of 53 (57%) were positive, with less pronounced expression than in adenocarcinomas.
  • Mesothelin expression showed no significant correlation with nodal status, tumor grade, or blood and lymph vessel infiltration.
  • In mice, 2 mg/kg twice weekly slowed tumor growth and prolonged survival but did not stop growth or shrink tumors.
  • In mice, 5 mg/kg healed 2 of 8 animals (25%) and fully stopped tumor growth in six. At 10 mg/kg the cure rate was 88% (7 of 8).
  • The mice showed no weight loss, but some developed ulcerations of the skin covering the tumor during treatment.
• The authors' conclusion: The authors concluded that the high mesothelin levels in cervical adenocarcinomas favour this tumor type as a target for mesothelin-directed therapies. They also concluded that affected women should be included in early clinical studies and that mesothelin staining should be considered a standard procedure in clinical routine.
• Limitations the authors state:
  • The authors noted that the drug binds human mesothelin (in the HeLa tumors) but not mouse mesothelin, so side effects in the mice were limited.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Glycoprotein, Pleura, Mesothelioma, Ovarian Cancer, Carcinoma, Adenocarcinoma, Squamous Cell Carcinoma.

Related studies

• Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect — S. Golfier, C. Kopitz, et al. (2014)
• Mesothelin Immunotherapy for Cancer: Ready for Prime Time? — R. Hassan, A. Thomas, et al. (2016)
• Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET — A.G. Terwisscha van Scheltinga, A. Ogasawara, et al. (2017)
• A multifunctional mesothelin antibody-tagged microparticle targets human mesotheliomas — S.L. Macura, J.M. Hillegass, et al. (2012)
• Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy — M. O'Hara, C. Stashwick, et al. (2016)
• Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial — H.L. Kindler, S. Novello, et al. (2022)

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