Mesothelin-targeted CAR-T cell therapy for solid tumors

Our plain-English summary of Mesothelin-targeted CAR-T cell therapy for solid tumors, by A. Klampatsa, V. Dimou, S.M. Albelda (Expert Opinion on Biological Therapy, 2021).

The study

• Authors: A. Klampatsa, V. Dimou, S.M. Albelda
• Journal: Expert Opinion on Biological Therapy
• Published: 2021;21(4):473-486
• Type of article: Review
• Cited by: 115 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Mesothelin (MSLN) is a tumor differentiation antigen normally restricted to the body's mesothelial surfaces, but significantly overexpressed in a broad range of solid tumors. For this reason, MSLN has emerged as an important target for the development of novel immunotherapies. This review focuses on anti-MSLN chimeric antigen receptor (CAR) T cell immunotherapy approaches.Areas covered: A brief overview of MSLN as a therapeutic target and existing anti-MSLN antibody-based drugs and vaccines is provided. A detailed account of anti-MSLN CAR-T cell approaches utilized in preclinical models is presented. Finally, a comprehensive summary of currently ongoing and completed anti-MSLN CAR-T cell clinical trials is discussed.Expert opinion: Initial trials using anti-MSLN CAR-T cells have been safe, but efficacy has been limited. Employing regional routes of delivery, introducing novel modifications leading to enhanced tumor infiltration and persistence, and improved safety profiles and combining anti-MSLN CAR-T cells with standard therapies, could render them more efficacious in the treatment of solid malignancies.

In plain English

This article was a review, not a new study. The authors described mesothelin, a protein normally found on the body's lining (mesothelial) surfaces but overexpressed in many cancers, including malignant mesothelioma. They reviewed treatments aimed at it, focusing on CAR-T cells, which are immune cells engineered to recognize mesothelin. They covered laboratory and animal studies, and clinical trials held since 2011. The article did not study or discuss asbestos exposure. In a University of Pennsylvania trial of 15 patients with malignant pleural mesothelioma, ovarian carcinoma or pancreatic cancer, the best overall response was stable disease, in 11 of 15. In the first trial in humans, one mesothelioma patient had a severe allergic reaction (anaphylaxis). A Memorial Sloan Kettering conference abstract reported results for 19 pleural mesothelioma patients given the cells into the chest. Of these, 2 had complete metabolic responses on PET scans, 5 had partial responses and 4 had stable disease. However, 14 of that trial's 21 patients had also later received anti-PD1 checkpoint drugs outside the trial protocol. The authors noted that relatively little trial data had been published. They concluded that early trials had been safe but efficacy had been limited.

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: Review of mesothelin-targeted therapies, focusing on anti-mesothelin CAR-T cells in preclinical models and clinical trials
• Who was studied: Published preclinical (cell and mouse) studies and early-stage clinical trials of anti-mesothelin CAR-T cells, conducted since 2011, in several mesothelin-positive solid tumors including malignant pleural mesothelioma
• Exposure: No asbestos exposure was studied. The 'exposure' is treatment with anti-mesothelin CAR-T cells (and, more briefly, other anti-mesothelin antibody drugs and vaccines).
• Main results:
  • In the cited University of Pennsylvania lentiviral trial (NCT02159716), 15 patients with malignant pleural mesothelioma, ovarian carcinoma or pancreatic ductal adenocarcinoma received a single infusion. The best overall response was stable disease in 11 of 15 patients.
  • In the cited first-in-human trial (NCT01355965) of four patients (three MPM, one PDAC), one MPM patient had a severe anaphylaxis reaction after an intravenous infusion.
  • In the cited Memorial Sloan Kettering trial (NCT02414269), cells were given into the chest (intrapleurally). A 2019 conference abstract reported best responses among the 19 MPM patients: 2 complete metabolic responses on PET scan, 5 partial responses and 4 stable disease.
  • In the same Memorial Sloan Kettering trial (21 patients treated), 14 patients later received anti-PD1 checkpoint blockade drugs off protocol, 6 to 17 weeks after the CAR-T infusion.
  • In the cited trial in chemotherapy-refractory metastatic pancreatic cancer (NCT01897415; 6 patients treated), two patients had stable disease, with progression-free survival of 3.8 and 5.4 months.
• The authors' conclusion: The authors concluded that initial trials of anti-mesothelin CAR-T cells had been safe but efficacy had been limited. They proposed that regional delivery, cell modifications and combination with standard therapies could improve results.
• Limitations the authors state:
  • The authors noted that, despite the many trials listed, relatively little data on their results had been published.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, CAR-T Cell, Immunotherapy, Clinical Trial.

Related studies

• Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors — A. Morello, M. Sadelain, et al. (2016)
• 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)
• High mesothelin expression by immunohistochemistry predicts improved survival in pleural mesothelioma — G.J. Chu, A. Linton, et al. (2023)
• Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors — J.J. Luke, F. Barlesi, et al. (2021)
• 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)
• 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)

Browse more research in Expert Opinion on Biological Therapy, or return to medical research.