Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM)

Our plain-English summary of Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM), by A. Klampatsa, A.R. Haas, E.K. Moon, et al (Cancers, 2017).

The study

• Authors: A. Klampatsa, A.R. Haas, E.K. Moon, S.M. Albelda
• Journal: Cancers
• Published: 2017;9(9)
• Type of article: Review
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease.

In plain English

This was a narrative review by authors at the University of Pennsylvania describing chimeric antigen receptor (CAR) T cell therapy for malignant pleural mesothelioma (MPM), which the article states is primarily caused by occupational or environmental inhalation exposure to asbestos and has a long latency period of 20-40 years. The review outlined adoptive cell therapy, CAR design (first-, second- and third-generation), and summarised preclinical work and Phase I trials targeting mesothelin and fibroblast activation protein (FAP), as well as potential targets pan-ErbB (T4), 5T4 and CSPG4. It reported that in one safety trial of transiently expressed anti-mesothelin CAR T cells (7 mesothelioma patients and 7 pancreatic cancer patients) no patient showed on-target, off-tumour toxicity, no consistent clinical responses were attained, two patients showed some evidence of tumour shrinkage, and one patient had an immediate serious anaphylactic reaction. In a later trial using a lentiviral vector (5 mesothelioma, 5 ovarian and 5 pancreatic cancer patients) the cells were well tolerated and detectable in blood for up to 30 days, with no clinical responses reported. The authors concluded that trials in mesothelioma are underway and their results will be used to improve later trials.

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 studies and clinical trials, which also includes the authors' own FAP immunostaining of two mesothelioma specimens
• Who was studied: Published preclinical models and Phase I clinical trials of CAR T cells in patients with malignant pleural mesothelioma (and some other solid tumours); the review also showed staining of two MPM tumour samples
• Exposure: CAR T cell therapy directed at tumour-associated antigens in MPM (mesothelin, FAP, pan-ErbB, 5T4, CSPG4); the disease itself attributed by the article to asbestos inhalation
• Main results:
  • In the first mesothelin CAR trial (NCT01355965; 7 mesothelioma and 7 pancreatic cancer patients) using transiently expressed CAR, no on-target/off-tumour toxicity occurred, no consistent clinical responses were attained, and two patients showed some evidence of tumour shrinkage
  • One patient in that trial had an immediate serious anaphylactic reaction during the third infusion, attributed to the murine SS1 scFv
  • In the lentiviral mesothelin CAR trial (NCT02159716; 5 mesothelioma, 5 ovarian, 5 pancreatic cancer patients), cells were well tolerated and detectable in blood for up to 30 days, with no clinical responses reported
  • The review stated that FAP is overexpressed in all three major MPM subtypes (epithelioid, sarcomatoid, biphasic)
  • The review cited reported CSPG4 overexpression in six out of eight MPM cell lines and in 25 out of 41 MPM biopsies
  • The review cited that 5T4-specific CD8+ T cells killed four out of six HLA-A2 positive MPM cell lines
• The authors' conclusion: The authors concluded that successes in haematological malignancies have prompted CAR T cell development for solid tumours such as MPM, that clinical trials are underway, and that their results will be used to improve subsequent trials
• Limitations the authors state:
  • The authors stated that the success seen in haematological malignancies has not yet been reproduced in solid tumours and listed obstacles such as poor trafficking, suppression by soluble mediators, checkpoint upregulation and antigen heterogeneity
  • Results of one of the mesothelin trials described were not yet published at the time of the review
  • The authors disclosed grant funding from Novartis to study CAR T cells

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunotherapy, Clinical Trial, Prognosis.

Related studies

• Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy — M. O'Hara, C. Stashwick, et al. (2016)
• Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies — S. Kiesgen, L. Chicaybam, et al. (2018)
• 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)
• Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer — J. Lv, R. Zhao, et al. (2019)
• Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors — S. Tomar, J. Zhang, et al. (2022)

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