Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors

Our plain-English summary of Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors, by A. Morello, M. Sadelain, P.S. Adusumilli (Cancer Discovery, 2016).

The study

• Authors: A. Morello, M. Sadelain, P.S. Adusumilli
• Journal: Cancer Discovery
• Published: 2016;6(2):133-46
• Type of article: Review
• Cited by: 417 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Chimeric antigen receptors (CAR) are synthetic receptors that target T cells to cell-surface antigens and augment T-cell function and persistence. Mesothelin is a cell-surface antigen implicated in tumor invasion, which is highly expressed in mesothelioma and lung, pancreas, breast, ovarian, and other cancers. Its low-level expression in mesothelia, however, commands thoughtful therapeutic interventions. Encouragingly, recent clinical trials evaluating active immunization or immunoconjugates in patients with pancreatic adenocarcinoma or mesothelioma have shown responses without toxicity. Altogether, these findings and preclinical CAR therapy models using either systemic or regional T-cell delivery argue favorably for mesothelin CAR therapy in multiple solid tumors.

Significance: Recent success obtained with adoptive transfer of CAR T cells targeting CD19 in patients with refractory hematologic malignancies has generated much enthusiasm for T-cell engineering and raises the prospect of implementing similar strategies for solid tumors. Mesothelin is expressed in a wide range and a high percentage of solid tumors, which we review here in detail. Mesothelin CAR therapy has the potential to treat multiple solid malignancies.

©2015 American Association for Cancer Research.

In plain English

This article was a review, not a new study. The authors reviewed published research on mesothelin, a protein found on cancer cells and at low levels on the normal lining of the chest, abdomen and heart. They assessed it as a target for CAR T cells, which are a patient's immune cells engineered to attack tumors. Asbestos exposure was not discussed. Among the work reviewed was the authors' own earlier series, which found mesothelin in 90% of 139 epithelioid malignant pleural mesotheliomas. In a reviewed trial, 77% of 13 mesothelioma patients given the drug SS1P with chemotherapy had partial responses. In a University of Pennsylvania trial of 4 patients with mesothelioma or pancreatic tumors, one patient had severe anaphylaxis and cardiac arrest after a third infusion. In the authors' mouse model of pleural mesothelioma, delivering the cells into the chest worked better than a 30-fold higher dose given into the bloodstream. The authors concluded that the findings argue favorably for this therapy in several solid tumors, while noting that its presence in normal tissue calls for caution.

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 laboratory, animal and clinical studies of mesothelin and mesothelin-targeted therapies
• Who was studied: No new patients were studied. The review drew on published literature, the authors' earlier patient series and mouse experiments, and listed clinical trials covering mesothelioma and lung, pancreatic, breast, ovarian and other cancers.
• Exposure: No asbestos or fiber exposure was studied. The review concerned treatments aimed at mesothelin: tumor vaccines (CRS-207), antibody-based therapies (SS1P immunotoxin, amatuximab, BAY 94-9343) and CAR T cells.
• Main results:
  • In the authors' earlier series (reference 21), mesothelin expression was found in 90% of 139 epithelioid malignant pleural mesotheliomas. The same series also covered lung adenocarcinoma, breast and esophageal cancers.
  • A reviewed phase I study (reference 42) reported partial responses in 77% of 13 patients with mesothelioma given SS1P together with cisplatin and pemetrexed.
  • A reviewed phase II trial (reference 45) gave amatuximab with pemetrexed and cisplatin to 89 patients with nonresectable pleural mesothelioma. Objective tumor response was reported in 40% and stable disease in 51%.
  • In a reviewed University of Pennsylvania trial, 4 patients with advanced mesothelioma or pancreatic tumors received mRNA mesothelin CAR T cells. The authors described multiple infusions as well tolerated, but one subject developed severe anaphylaxis and cardiac arrest after the third infusion.
  • In the authors' orthotopic mouse model of malignant pleural mesothelioma (reference 52), CAR T cells delivered into the pleural space led to greater T-cell proliferation, tumor eradication and survival than a 30-fold higher dose given systemically.
• The authors' conclusion: The authors concluded that clinical findings with mesothelin-targeted therapies, together with preclinical CAR models using systemic or regional delivery, argue favorably for mesothelin CAR therapy in multiple solid tumors.
• Limitations the authors state:
  • The authors noted that mesothelin is also present at low levels in normal mesothelium (the lining tissue), which calls for careful treatment approaches.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelioma, Clinical Trial, Adenocarcinoma.

Related studies

• Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy — M. O'Hara, C. Stashwick, et al. (2016)
• Clinical Evaluation of ErbB-Targeted CAR T-Cells, Following Intracavity Delivery in Patients with ErbB-Expressing Solid Tumors — S. Papa, M. van Schalkwyk, et al. (2015)
• Mesothelin-targeted CAR-T cell therapy for solid tumors — A. Klampatsa, V. Dimou, et al. (2021)
• 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)
• 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 agents in clinical trials and in preclinical development — R.J. Kelly, E. Sharon, et al. (2012)

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