Immunotherapeutic Approaches in Malignant Pleural Mesothelioma

Our plain-English summary of Immunotherapeutic Approaches in Malignant Pleural Mesothelioma, by R. Terenziani, S. Zoppi, C. Fumarola, et al (Cancers, 2021).

The study

• Authors: R. Terenziani, S. Zoppi, C. Fumarola, R. Alfieri, M. Bonelli
• Journal: Cancers
• Published: 2021;13(11)
• Type of article: Review
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the intrinsic chemo-resistance of the tumor. Another relevant point is the absence of approved therapies in the second line setting following progression of MPM after chemotherapy. Considering the poor prognosis of the disease and the fact that the incidence of this tumor is expected to increase in the next decade, novel therapeutic approaches are urgently needed. In the last few years, several studies have investigated the efficacy and safety of immune-checkpoint inhibitors (ICIs) in the treatment of unresectable advanced MPM, and a number of trials with immunotherapeutic agents are ongoing in both first line and second line settings. In this review, we describe the most promising emerging immunotherapy treatments for MPM (ICIs, engineered T cells to express chimeric antigen receptors (CARs), dendritic cells (DCs) vaccines), focusing on the biological and immunological features of this tumor as well as on the issues surrounding clinical trial design.

In plain English

This article was a review of immunotherapy treatments for malignant pleural mesothelioma (MPM), a cancer the authors described as commonly associated with asbestos exposure. The review did not study asbestos exposure itself. It summarized trials of immune checkpoint inhibitors, CAR-T cell therapy and cancer vaccines. In the CheckMate 743 trial of 605 previously untreated patients with unresectable MPM, median overall survival was 18.1 months with nivolumab plus ipilimumab versus 14.1 months with chemotherapy, leading to 2020 FDA approval for such patients. In the DETERMINE trial of 571 patients, tremelimumab did not significantly improve overall survival compared with placebo. In the PROMISE-meso trial, pembrolizumab did not prove superior to chemotherapy. Preliminary results from 25 MPM patients in a mesothelin-targeted CAR-T trial showed a 36.8% overall response rate among those given CAR-T cells, cyclophosphamide and at least three doses of pembrolizumab, a subgroup whose size the review did not state. The authors concluded that recent studies had failed to show an evident advantage of checkpoint inhibitors over chemotherapy, and that further studies are needed to confirm their efficacy in 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 preclinical studies and clinical trials of immunotherapy in malignant pleural mesothelioma (no search method described)
• Who was studied: Published and ongoing studies of immunotherapy in malignant pleural mesothelioma, including clinical trials listed on clinicaltrials.gov (accessed 28 April 2021), as well as laboratory and mouse studies
• Exposure: Immunotherapy treatments: immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1/PD-L1, LAG-3, TIM-3, VISTA), CAR-T cells and cancer vaccines including dendritic cell vaccines. Asbestos exposure was mentioned only as background on the cause of MPM.
• Main results:
  • The review reported that in the CheckMate 743 trial (605 participants with unresectable, previously untreated MPM), median overall survival was 18.1 months with nivolumab plus ipilimumab versus 14.1 months with chemotherapy, and that this led to 2020 FDA approval for patients with previously untreated unresectable MPM
  • The review reported that in the DETERMINE trial (571 patients with pleural or peritoneal malignant mesothelioma), tremelimumab did not significantly improve overall survival compared with placebo
  • The review reported that in the PROMISE-meso trial in relapsed MPM, median progression-free survival was 2.5 months with pembrolizumab versus 3.4 months with chemotherapy, and pembrolizumab did not prove superior to chemotherapy
  • The review reported preliminary results from 25 MPM patients in a mesothelin-targeted CAR-T trial (NCT02414269). Patients who received CAR-T cells, cyclophosphamide and at least three doses of pembrolizumab had an overall response rate of 36.8% and a disease control rate of 57.8%. The review did not state how many patients were in this subgroup.
• The authors' conclusion: The authors concluded that recent clinical studies had failed to show an evident advantage of immune checkpoint inhibitors over chemotherapy for most patients, that predictive markers of response are needed, and that further studies are needed to confirm their efficacy in MPM
• Limitations the authors state:
  • The authors noted that most checkpoint inhibitor trials were first run in patients who had already progressed after earlier treatment, and that the limited life span of these patients could explain the poor or absent benefit
  • The authors noted that PD-L1 expression did not emerge as a marker that predicts which patients respond to checkpoint inhibitors

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelium, Asbestos Exposure, Cisplatin, Pemetrexed (Alimta), Chemotherapy, Prognosis, checkpoint inhibitors.

Related studies

• Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma — A.J. Bograd, K. Suzuki, et al. (2011)
• Expression and regulation of B7-H3 immunoregulatory receptor, in human mesothelial and mesothelioma cells: immunotherapeutic implications — L. Calabrò, L. Sigalotti, et al. (2011)
• Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells — M. Bonelli, R. Terenziani, et al. (2020)
• Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways — N.H. Heintz, Y.M. Janssen-Heininger, et al. (2010)
• New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents — A.K. Nowak, R.A. Lake, et al. (2002)
• Gene therapy approaches for inherited and acquired lung diseases — D.T. Curiel, J.M. Pilewski, et al. (1996)

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