CAR T-cell therapy for lung cancer and malignant pleural mesothelioma

Our plain-English summary of CAR T-cell therapy for lung cancer and malignant pleural mesothelioma, by M. Zeltsman, J. Dozier, E. McGee, et al (Translational Research, 2017).

The study

• Authors: M. Zeltsman, J. Dozier, E. McGee, D. Ngai, P.S. Adusumilli
• Journal: Translational Research
• Published: 2017;187:1-10
• Type of article: Review
• Cited by: 78 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Immunotherapy is a promising field that harnesses the power of the immune system as a therapeutic agent for cancer treatment. Beneficial outcomes shown in patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) with relatively higher tumor-infiltrating T cells, combined with impressive responses obtained in a cohort of patients with NSCLC following checkpoint blockade therapy, lays a strong foundation to promote effector immune responses in these patients. One such approach being investigated is administration of tumor antigen-targeted T cells with transduction of a chimeric antigen receptor (CAR). CARs are synthetic receptors that enhance T-cell antitumor effector function and have gained momentum to investigate in solid tumors based on recent successes of clinical trials treating patients with B-cell hematologic malignancies. This review summarizes target antigens for CAR T-cell therapy that are being investigated in preclinical studies and clinical trials for both NSCLC and MPM patients. We discuss the rationale for combination immunotherapies for NSCLC and MPM patients. Additionally, we have highlighted the challenges and strategies for overcoming the obstacles facing translation of CAR T-cell therapy to solid tumors.

Copyright © 2017 Elsevier Inc. All rights reserved.

In plain English

This was a review article. It did not study asbestos exposure; its introduction notes that malignant pleural mesothelioma (MPM) is commonly associated with previous asbestos exposure. The review summarized CAR T-cell therapy, in which T cells carry a synthetic receptor aimed at a tumor antigen, as it was being investigated in preclinical studies and clinical trials for non-small cell lung cancer and MPM. It described target antigens. These included mesothelin, which the authors said is expressed at low levels on normal mesothelial cells but overexpressed in most MPM. Another was fibroblast activation protein, reported as overexpressed in all three major MPM subtypes. A table listed current trials registered on ClinicalTrials.gov. The review also described earlier studies. One was a University of Pennsylvania trial that treated four patients; one patient had a serious anaphylactic reaction. Others were the authors' own mouse experiments, in which giving mesothelin-targeted CAR T cells into the pleural space worked significantly better than systemic delivery. The authors concluded that CAR T-cell therapy is a rapidly growing and promising approach for lung cancer and MPM.

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 CAR T-cell therapy for lung cancer and malignant pleural mesothelioma (no original data collection; no search method stated)
• Who was studied: Preclinical studies and clinical trials of CAR T-cell therapy for non-small cell lung cancer and malignant pleural mesothelioma, including a table of current trials listed on ClinicalTrials.gov
• Exposure: Not an asbestos exposure study. The treatment reviewed is CAR T-cell therapy. Asbestos is mentioned only as background: MPM is described as commonly associated with previous asbestos exposure.
• Main results:
  • The review described mesothelin as a target antigen: expressed at low levels on normal mesothelial cells of the pleura, pericardium, peritoneum and tunica vaginalis, and overexpressed in the majority of MPM, lung, pancreatic and ovarian carcinomas
  • As reported from an earlier University of Pennsylvania trial (not this review's own data): four patients with MPM or metastatic pancreatic cancer received repeat doses of transiently expressed mesothelin-targeted CAR T cells, and moderate clinical responses were observed
  • In that same earlier trial, one patient had a serious anaphylactic reaction shortly after a third infusion, attributed to the mouse-derived part of the CAR construct
  • In the authors' earlier mouse model of MPM, intrapleural delivery of mesothelin-targeted CAR T cells gave significantly enhanced antitumor efficacy and functional T-cell persistence compared with systemic delivery. This was the basis for their phase I trial of intrapleural delivery (NCT02414269).
  • In the authors' earlier mouse model work, mesothelin CAR T cells became exhausted and nonfunctional after repeated antigen exposure. The review attributed this to PD-1 upregulation and reported that PD-1 checkpoint blockade could rescue the cells.
  • Fibroblast activation protein was described as overexpressed in all three major MPM subtypes (epitheloid, sarcomatoid and biphasic). A University of Zurich phase I trial was described as testing FAP-targeted CAR T cells given into the pleural effusion of MPM patients.
• The authors' conclusion: The authors concluded that CAR T-cell therapy is a rapidly growing and promising immunotherapeutic approach for solid tumors such as lung cancer and MPM. They also wrote that barriers such as T-cell trafficking and a hostile tumor microenvironment can be addressed by fine-tuning the CAR construct, armoring it, and exploring combination therapies.

Topics

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

Medical terms in this study, explained in our Lexicon: Lung Cancer, Pleural Mesothelioma, Immunotherapy, Non-Small Cell Lung Cancer, Clinical Trial.

Related studies

• A regional approach for CAR T-cell therapy for mesothelioma: from mouse models to clinical trial — M. Mayor, M. Zeltsman, 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)
• T cells expressing chimeric antigen receptors can cause anaphylaxis in humans — M.V. Maus, A.R. Haas, et al. (2013)
• Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1) — U. Petrausch, P.C. Schuberth, et al. (2012)
• Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies — S. Kiesgen, L. Chicaybam, et al. (2018)
• NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis — J.P. Lai, P.F. Robbins, et al. (2012)

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