Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy

Our plain-English summary of Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy, by M. O'Hara, C. Stashwick, A.R. Haas, et al (Immunotherapy, 2016).

The study

• Authors: M. O'Hara, C. Stashwick, A.R. Haas, J.L. Tanyi
• Journal: Immunotherapy
• Published: 2016;8(4):449-60
• Type of article: Review
• Cited by: 66 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelin is a promising target for immune-based therapy, specifically for mesothelioma and pancreatic and ovarian cancers that have high levels of mesothelin expression. Many preclinical and clinical studies that target tumors with high mesothelin expression with antibodies, immunotoxins, antibody-drug conjugates and vaccines have shown the potential of mesothelin as a target. Studies of T cells genetically modified with chimeric antigen receptors (CAR) report significant efficacy in hematologic malignancies, and antimesothelin CAR T cells are currently being investigated in clinical studies. Here we outline the rationale for using mesothelin as a target for immunotherapy, review the clinical and preclinical studies evaluating mesothelin-directed therapies and explore the promise of CAR T cells directed against mesothelin for immunotherapy in the future.

In plain English

This article was a review, not a new study. The authors described mesothelin, a protein found on normal mesothelial cells. They noted it is found on nearly 100% of epithelioid mesotheliomas but at low levels in the sarcomatoid type, and is overexpressed in the majority of pancreatic adenocarcinomas and serous ovarian cancers. They reviewed earlier trials of an immunotoxin (SS1P), an antibody (amatuximab), a mesothelin-expressing vaccine (CRS-207) and an antibody–drug conjugate aimed at mesothelin, plus GVAX, a vaccine that is not mesothelin-specific. In one cited trial, SS1P combined with pemetrexed and cisplatin in mesothelioma patients gave a 60% partial response rate. In another, amatuximab with the same chemotherapy gave partial responses in 40% of patients and stable disease in 51%. The authors then reviewed early work on mesothelin-directed CAR T cells, which are T cells genetically modified to recognize mesothelin. Cited reports described safety in two patients, stable disease in two of six pancreatic cancer patients in one study, and anaphylaxis in one patient in another. The authors concluded that CAR T-cell therapy against mesothelin is a promising strategy. The article does not discuss asbestos.

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 preclinical and clinical studies of mesothelin-directed therapies, including CAR T cells
• Who was studied: No new patients were studied. The review covered published trials and preclinical studies, mainly in patients with mesothelioma, pancreatic cancer and ovarian cancer.
• Exposure: Not an asbestos exposure study. The 'exposures' reviewed were mesothelin-directed treatments: antibodies, immunotoxins, antibody–drug conjugates, vaccines and CAR T cells.
• Main results:
  • Cited studies found mesothelin on nearly 100% of epithelioid mesotheliomas, but expression is low in the sarcomatoid variant.
  • The authors stated that mesothelin is overexpressed in about 30% of all cancers, including the majority of epithelioid mesotheliomas, pancreatic adenocarcinomas and serous ovarian cancers.
  • GVAX, a pancreatic cancer vaccine, is not mesothelin-specific, but mesothelin-specific T-cell responses have been noted with it.
  • In a cited Phase I trial of bolus SS1P in 34 patients with advanced mesothelioma, ovarian cancer or pancreatic cancer, four patients had minor responses, 19 had stable disease and ten had progressive disease.
  • In a cited Phase 1 study of SS1P with pemetrexed and cisplatin in treatment-naive mesothelioma patients (24 in Table 1), safety was good and the partial response rate was 60%.
  • In a cited Phase II trial of amatuximab with cisplatin and pemetrexed in unresectable mesothelioma patients (89 in Table 1), 40% had partial responses and 51% had stable disease.
  • For context, the authors cited the only randomized, double-blind, placebo-controlled trial they say showed a survival benefit in mesothelioma: pemetrexed plus cisplatin raised median survival from 9.3 to 12.1 months.
  • In a cited Phase I trial of the CRS-207 vaccine, the best response was stable disease in four of 13 evaluable patients, and 37% of patients were alive more than 15 months.
  • A cited report of mRNA CAR T cells against mesothelin, given to one patient with mesothelioma and one with metastatic pancreatic adenocarcinoma, described safety.
  • In a cited Phase I study of mRNA CAR T cells in six patients with pancreatic adenocarcinoma, two of the six had stable disease.
  • In a cited mRNA CAR T-cell Phase I study, one patient had anaphylaxis, attributed to prior exposure and sensitization.
  • Preliminary results of a Phase I trial of lentiviral CAR T cells against mesothelin reported that a single infusion was well tolerated, without cytokine release syndrome, in patients with mesothelioma and ovarian and pancreatic cancer.
• The authors' conclusion: The authors concluded that CAR T-cell therapy directed against mesothelin is a promising therapeutic strategy for mesothelin-expressing cancers.

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, Mesothelioma, Ovarian Cancer, Immunotherapy.

Related studies

• Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies — G.L. Beatty, A.R. Haas, et al. (2014)
• T cells expressing chimeric antigen receptors can cause anaphylaxis in humans — M.V. Maus, A.R. Haas, et al. (2013)
• Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies — S. Kiesgen, L. Chicaybam, et al. (2018)
• A regional approach for CAR T-cell therapy for mesothelioma: from mouse models to clinical trial — M. Mayor, M. Zeltsman, et al. (2016)
• Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors — A. Morello, M. Sadelain, et al. (2016)
• Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy — R. Hassan, C. Schweizer, et al. (2010)

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