Mesothelin Immunotherapy for Cancer: Ready for Prime Time?

Our plain-English summary of Mesothelin Immunotherapy for Cancer: Ready for Prime Time?, by R. Hassan, A. Thomas, C. Alewine, et al (Journal of Clinical Oncology, 2016).

The study

• Authors: R. Hassan, A. Thomas, C. Alewine, D.T. Le, E.M. Jaffee, I. Pastan
• Journal: Journal of Clinical Oncology
• Published: 2016;34(34):4171-4179
• Type of article: Review
• Cited by: 291 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer.

In plain English

This article is a review, not a new study. The authors described mesothelin, a protein found on many cancers, and reviewed treatments aimed at it that were being tested in clinical trials, mostly for malignant mesothelioma, pancreatic cancer and ovarian cancer. In studies the authors cited, mesothelin was found in 290 of 352 mesotheliomas. The authors said sarcomatoid mesotheliomas are not eligible for these treatments because they lack mesothelin. The review summarized earlier trials in mesothelioma. With the drug SS1P plus chemotherapy, 12 of 20 evaluable patients (60%) had tumor responses. With SS1P after immune-suppressing drugs, 3 of 10 had major, long-lasting regressions. In a trial of amatuximab plus chemotherapy in 89 pleural mesothelioma patients, 40% responded, but the trial did not meet its main goal. With anetumab ravtansine, 5 of 16 patients (31%) responded. With the vaccine CRS-207 plus chemotherapy, 20 of 34 evaluable patients (59%) had partial responses. The authors concluded that there had been substantial progress, and noted that two drugs were in registration trials for mesothelioma.

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 mesothelin-targeted cancer therapies and ongoing clinical trials
• Who was studied: published and ongoing clinical trials of mesothelin-targeted agents, mainly in patients with malignant mesothelioma, pancreatic cancer and ovarian cancer; also lung adenocarcinoma
• Exposure: mesothelin-targeted treatments: immunotoxins (SS1P, LMB-100), a chimeric antibody (amatuximab), antibody-drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), Listeria-based vaccines (CRS-207, JNJ-64041757) and CAR T cells; asbestos exposure is not discussed
• Main results:
  • In studies compiled in the review's Table 1, mesothelin expression was found in 290 of 352 mesotheliomas (82%), in 248 of 261 epithelioid mesotheliomas (95%) and in 0 of 23 sarcomatoid mesotheliomas (0%)
  • The authors stated that sarcomatoid mesotheliomas are not eligible for mesothelin-directed therapies because they lack mesothelin expression
  • In a cited trial of SS1P with pemetrexed and cisplatin as first-line therapy for pleural mesothelioma, 12 of 20 evaluable patients (60%) had objective tumor responses and three had stable disease
  • In a cited pilot study of pentostatin and cyclophosphamide before SS1P in mesothelioma patients for whom standard therapies had failed, two of 10 patients developed anti-SS1P antibodies after the first cycle, compared with 88% of patients in prior studies of SS1P alone
  • In the same pilot study, three of 10 evaluable patients had major cancer regressions that were long lasting
  • In a cited nonrandomized phase II trial of amatuximab with pemetrexed and cisplatin in 89 patients with malignant pleural mesothelioma, the objective response rate by independent radiologic review was 40%, 51% had stable disease, and the overall disease control rate was 91%
  • The amatuximab trial did not meet its primary end point of a 6-month PFS response rate of 62%; overall survival was 14.8 months, which the authors described as better than historical controls with pemetrexed and cisplatin alone
  • In a cited phase I trial of anetumab ravtansine, five of 16 mesothelioma patients treated at the maximum tolerated dose (31%) had objective tumor responses and seven (44%) had stable disease
  • In a cited phase Ib trial of CRS-207 plus pemetrexed and cisplatin in pleural mesothelioma, 20 of 34 evaluable patients (59%) had objective partial responses and 12 (35%) had stable disease, for a disease control rate of 94%
  • In the SS1P phase I trials, the dose-limiting toxicity was pleuritis, but patients did not develop pericarditis
  • At the time of the review, two mesothelin-targeted drugs (amatuximab and anetumab ravtansine) were in multicenter registration clinical trials for malignant mesothelioma
• The authors' conclusion: The authors concluded that there had been substantial progress in developing different approaches to target mesothelin for cancer therapy, and that ongoing trials would define its usefulness
• Limitations the authors state:
  • The authors did not cover CAR T-cell clinical trials in detail, citing other recent reviews

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Immunotherapy, Malignant Mesothelioma, Lung Adenocarcinoma, Mesothelial Cells, CRS-207, Second-Line Therapy, Clinical Trial.

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• 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-targeted agents in clinical trials and in preclinical development — R.J. Kelly, E. Sharon, et al. (2012)
• Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy? — D. Signorelli, M. Macerelli, 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)
• Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors — E. Hatterer, X. Chauchet, et al. (2020)

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