Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Our plain-English summary of Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma, by D. Yeo, L. Castelletti, N. van Zandwijk, et al (Cancers, 2021).

The study

• Authors: D. Yeo, L. Castelletti, N. van Zandwijk, J.E.J. Rasko
• Journal: Cancers
• Published: 2021;13(16)
• Type of article: Review
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody-drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

In plain English

This article was a review, not a new study. The authors summarized published research and clinical trials on mesothelin, a protein found at high levels in malignant pleural mesothelioma, and stated that no new data were created or analyzed. The review did not study asbestos exposure itself, but it did review whether a blood marker could screen asbestos-exposed people. The authors described a meta-analysis of over 4000 patients that estimated the sensitivity and specificity of this marker, SMRP, at 47% and 95%. They noted that studies in asbestos-exposed populations had failed to show its value as a screening tool. They also reviewed mesothelin-targeted treatments tested in trials, including antibodies, antibody–drug conjugates, immunotoxins, a vaccine and CAR T cells. The authors concluded that SMRP has high specificity but lacks sensitivity for diagnosis, screening and prognosis, though it is useful for monitoring response to therapy. Earlier in the review, they described this monitoring role for patients whose SMRP level was elevated at first. They also concluded that clinical responses to mesothelin-directed treatments had so far been modest.

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: Narrative review of published studies and clinical trials on mesothelin as a biomarker and treatment target in malignant pleural mesothelioma; no new data
• Who was studied: Published clinical studies and registered clinical trials (listed in the article's Table 1) that examined mesothelin in malignant pleural mesothelioma patients; the authors analyzed no new patient data
• Exposure: Not an asbestos exposure study. The review covered mesothelin-based markers (SMRP and MPF) and mesothelin-targeted treatments. Asbestos enters in two ways: as background on who develops malignant pleural mesothelioma, and in the review of whether blood SMRP could screen asbestos-exposed, high-risk people. No fiber types are discussed.
• Main results:
  • The review cited a meta-analysis of over 4000 patients that estimated the sensitivity of blood SMRP for diagnosing malignant pleural mesothelioma at 47% and its specificity at 95%. This is a reviewed study, not this article's own data.
  • According to the review, prospective and retrospective studies in asbestos-exposed populations had failed to show the value of blood SMRP as a screening tool
  • The review cited a meta-analysis of 8 studies involving 579 malignant pleural mesothelioma patients in which high SMRP levels coincided with worse survival. The authors noted that some other studies could not confirm this.
  • According to the reviewed studies, a 10% reduction in serum SMRP level was associated with radiological response. The authors described a role for serum SMRP monitoring in patients who initially presented with an elevated SMRP level.
  • Reviewed studies of mesothelin in tumor tissue disagreed on survival. One study of 38 patients suggested shorter survival with high expression, while a study of 91 patients found high expression associated with longer survival.
  • A reviewed single-arm phase II trial gave amatuximab with pemetrexed/cisplatin to patients with unresectable malignant pleural mesothelioma (n = 83). It reported an overall survival of 14.8 months and a disease control rate of 90.4% (39.8% partial response, 50.6% stable disease).
  • A reviewed randomized phase II trial in malignant pleural mesothelioma patients (96% epithelioid) compared second-line anetumab ravtansine with vinorelbine. Anetumab ravtansine did not increase progression-free survival.
  • In a reviewed CAR T cell trial (NCT02414269), 2 of 16 patients had partial response, 9 had stable disease and 5 had progressive disease
  • The authors judged that clinical responses to mesothelin-directed immunotherapies had so far been modest
• The authors' conclusion: The authors concluded that serum SMRP has high specificity but lacks sensitivity for diagnosing, screening for and predicting the outcome of malignant pleural mesothelioma. They concluded it is useful for monitoring response to therapy because it is associated with tumor volume.
• Limitations the authors state:
  • The authors noted that mesothelin and MPF are negative in the sarcomatoid subtype of mesothelioma
  • The authors noted that SMRP serum levels are influenced by age, kidney function, genetic background and body mass index. This may cause false-positive results if SMRP is used alone.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Biomarker, Pleural Mesothelioma, Prognosis, Pleura, Glycoprotein, Immunotherapy, Monoclonal Antibody.

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