Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy

Our plain-English summary of Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy, by R. Hassan, C. Schweizer, K.F. Lu, et al (Lung Cancer, 2010).

The study

• Authors: R. Hassan, C. Schweizer, K.F. Lu, B. Schuler, A.T. Remaley, S.C. Weil, I. Pastan
• Journal: Lung Cancer
• Published: 2010;68(3):455-9
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Mesothelin, a tumor differentiation antigen highly expressed in mesothelioma and ovarian cancer, is the receptor for CA-125 (MUC 16) and this interaction may play a role in tumor metastasis. MORAb-009 is a chimeric anti-mesothelin monoclonal antibody.

Methods: Twenty-four patients with mesothelin expressing cancers were treated on a phase I study of MORAb-009 administered as an intravenous infusion (12.5-400mg/m(2)) weeklyx4 doses with 2 weeks off before the next cycle. This report summarizes the effect of MORAb-009 on serum CA-125 kinetics in the eight patients with mesothelioma who had CA-125 levels measured before and at different time-points following therapy.

Results: MORAb-009 treatment led to a marked increase in serum CA-125 levels in all patients including those without elevated CA-125 levels before therapy. The increase in CA-125 levels was not due to disease progression since CA-125 levels decreased rapidly after stopping MORAb-009 therapy. No patients had signs of peritoneal or pleural inflammation as the possible cause of CA-125 rise. In addition, the elevated CA-125 levels were not due to MORAb-009 interfering with the laboratory assay used to measure CA-125.

Conclusion: The increase in serum CA-125 produced by treatment with MORAb-009 is most likely due to MORAb-009 inhibiting the binding of tumor shed CA-125 to mesothelin present on mesothelial cells lining the pleural and peritoneal cavities. Inhibiting the mesothelin-CA-125 interaction could be a useful strategy to prevent tumor metastasis in mesotheliomas and ovarian cancer.

Published by Elsevier Ireland Ltd.

In plain English

This report came from a phase I dose-escalation trial of MORAb-009, an experimental antibody that targets mesothelin, a protein found on mesothelioma cells. The article does not discuss asbestos. It described serum CA-125, a blood tumor marker, in the eight mesothelioma patients treated at the National Cancer Institute: four with pleural and four with peritoneal mesothelioma, all of the epithelial subtype and all previously treated with chemotherapy. They received doses from 12.5 to 400 mg/m2. CA-125 rose in all eight patients after treatment, including the two whose levels were normal (0 to 35 U/ml) beforehand. In one of them it went from 8 to 110 U/ml after a single infusion. In two patients followed longer, levels fell after treatment stopped. Adding the antibody to serum samples did not change the test results, and no patient had clinical signs of pleuritis or peritonitis. The authors concluded that the rise was likely caused by the antibody blocking CA-125 from binding to mesothelin. They suggested that CA-125 is not useful for tracking tumor progression during this treatment. CA-125 testing was not part of the trial protocol.

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: Report of serum CA-125 measurements from a subset of patients in a three-institution phase I dose-escalation clinical trial of the anti-mesothelin antibody MORAb-009, plus a laboratory test of whether the antibody interferes with the CA-125 assay
• Who was studied: 8 patients with mesothelioma treated at the National Cancer Institute (USA): 6 men and 2 women aged 51 to 70. Four had pleural and four had peritoneal mesothelioma, all of the epithelial subtype, and all had failed prior chemotherapy. They were part of 24 patients with mesothelin-expressing cancers treated in the trial. Dates of treatment are not given.
• Exposure: No asbestos exposure is reported. The exposure studied was treatment with MORAb-009, a chimeric anti-mesothelin monoclonal antibody, given by weekly intravenous infusion for 4 weeks with 2 weeks off, at doses from 12.5 to 400 mg/m2.
• Main results:
  • Before treatment, serum CA-125 was elevated in 6 of the 8 patients; patients 1002 and 1007 had levels in the normal range.
  • All 8 patients had a rise in serum CA-125 after MORAb-009 treatment, in both pleural and peritoneal mesothelioma.
  • In patient 1007, whose level was normal before treatment, CA-125 rose from 8 U/ml to 110 U/ml after one infusion. In patient 1002, also normal before treatment, it rose to 47 U/ml by day 35.
  • In patient 1003 (peritoneal), CA-125 rose more than 15-fold to 752 U/ml on day 22, fell to 495 U/ml on day 49, and was close to pre-treatment values on day 176. In patient 1005 (pleural), with a baseline of 399 U/ml, the level peaked at 882 U/ml on day 83 and was 466 U/ml by day 120.
  • Adding MORAb-009 (or the control antibody rituximab) to serum samples from two ovarian cancer patients did not interfere with CA-125 measurement.
  • None of the patients had clinical signs of pleuritis or peritonitis.
  • Of the 6 patients evaluable for tumor response, 4 had stable disease and 2 had progressive disease.
  • The authors stated that their results suggest serum CA-125 is not useful for assessing tumor progression in mesothelioma patients treated with MORAb-009.
• The authors' conclusion: The authors concluded that the rise in serum CA-125 during MORAb-009 therapy was likely due to the antibody blocking CA-125 from binding to mesothelin. They suggested that inhibiting this interaction could be a strategy against tumor spread in mesothelioma and ovarian cancer, and said clinical trials are needed to determine whether it gives clinical benefit.
• Limitations the authors state:
  • CA-125 was not measured serially at the other two trial sites, so data were available only for the 8 NCI patients.
  • CA-125 measurement was not part of the trial protocol.
  • Serum mesothelin could not be measured because MORAb-009 interferes with the mesothelin assay.
  • Applying the finding to ovarian cancer patients would require a formal analysis of CA-125 in that group.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Ovarian cancer.

Medical terms in this study, explained in our Lexicon: Mesothelin, CA-125, Mesothelioma, Monoclonal Antibody, Ovarian Cancer, Metastasis, Disease Progression, Inflammation.

Related studies

• A novel PET imaging using ⁶⁴Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells — K. Kobayashi, T. Sasaki, et al. (2015)
• Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo — K. Inami, M. Abe, et al. (2010)
• 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 — A. Gupta, Z. Hussein, et al. (2016)
• Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy — M. O'Hara, C. Stashwick, et al. (2016)
• Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors — Y. Fujisaka, T. Kurata, et al. (2015)
• Anti-CTLA-4 therapy for malignant mesothelioma — A. Guazzelli, E. Bakker, et al. (2017)

Browse more research in Lung Cancer, or return to medical research.