Immune checkpoint blockade in malignant mesothelioma

Our plain-English summary of Immune checkpoint blockade in malignant mesothelioma, by L. Calabrò, M. Maio (Seminars in Oncology, 2015).

The study

• Authors: L. Calabrò, M. Maio
• Journal: Seminars in Oncology
• Published: 2015;42(3):418-22
• Type of article: Review
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a highly aggressive malignancy with a very dismal prognosis. Current treatment for unresectable MM is largely unsatisfactory; therefore, new therapeutic approaches are eagerly awaited. A better understanding of the complex mechanisms of immune escape operated by neoplastic cells and the ability to unleash an efficient anti-tumor immune response by targeting regulatory immune checkpoint(s) with immunomodulatory monoclonal antibodies (mAbs), is leading to very promising clinical results in different tumor types. Herein, we highlight the clinical impact so far identified for these new immunomodulatory agents in MM patients and discuss their prospective use to design novel clinical trials.

Copyright © 2015 Elsevier Inc. All rights reserved.

In plain English

This was a review of immune checkpoint treatment for malignant mesothelioma by authors who ran the trials described. It did not study asbestos exposure. It summarized two Italian trials of tremelimumab, an antibody blocking CTLA-4. The 2008 trial enrolled patients who had failed a first-line platinum-based regimen; the 2012 trial enrolled patients progressing on one. In MESOT-TREM-2008, 29 patients received 15 mg/kg every 90 days. Objective responses occurred in 2 of 29, and 24% had disease stabilization. Median overall survival was 10.7 months, with 1- and 2-year survival rates of 48% and 37%. Grade 3 or 4 immune-related side effects occurred in 14% of patients. In MESOT-TREM-2012, 29 patients received 10 mg/kg every 4 weeks for six induction cycles, then every 12 weeks. Preliminary results showed immune-related partial responses in 4 of 29 and median overall survival of 11.3 months. The authors reported high PD-L1 expression in 6 of 9 mesothelioma cell lines. They noted that standard tumor-measurement criteria are hard to apply to mesothelioma. The authors concluded that CTLA-4 blockade is a highly promising strategy in mesothelioma.

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 immune checkpoint blockade in malignant mesothelioma, mainly summarizing the authors' own earlier trials of tremelimumab, which were published separately
• Who was studied: Malignant mesothelioma patients in two Italian trials. MESOT-TREM-2008 (started May 2009) enrolled 29 patients who had failed a first-line platinum-based regimen. MESOT-TREM-2012 (enrolment July 2012 to July 2013) enrolled 29 patients progressing on a first-line platinum-based chemotherapy regimen. The authors also studied a panel of human mesothelioma cell lines.
• Exposure: No asbestos exposure was studied. The treatment reviewed was the anti-CTLA-4 antibody tremelimumab: 15 mg/kg every 90 days in MESOT-TREM-2008, and 10 mg/kg every 4 weeks for six cycles in an induction phase, then every 12 weeks in a maintenance phase, in MESOT-TREM-2012
• Main results:
  • MESOT-TREM-2008: objective responses in 2 of 29 patients
  • MESOT-TREM-2008: disease stabilization (median duration 12.4 months) in 24% of treated patients
  • MESOT-TREM-2008: median overall survival 10.7 months; 1- and 2-year survival rates 48% and 37%
  • MESOT-TREM-2008: dermatological and gastrointestinal immune-related adverse events in 62% and 31% of patients
  • MESOT-TREM-2008: grade 3 or 4 immune-related adverse events in 14% of patients
  • MESOT-TREM-2008: blood levels of a T-cell subpopulation (CD4+ ICOS+) rose during treatment and were significantly associated with better survival in the early phases of treatment
  • MESOT-TREM-2012 (preliminary, median follow-up 14.5 months): immune-related partial response in 4 of 29 patients
  • MESOT-TREM-2012 (preliminary): 51.7% immune-related disease control rate and median overall survival 11.3 months
  • MESOT-TREM-2012: no increase in grade 3 to 4 immune-related adverse events was observed
  • In the authors' laboratory work, PD-L1 was expressed to a high degree in 6 of 9 human mesothelioma cell lines
• The authors' conclusion: The authors concluded that CTLA-4 blockade represents a highly promising therapeutic strategy in mesothelioma. They added that immune checkpoint blockade is being actively explored in mesothelioma and will hopefully improve patient outcomes.
• Limitations the authors state:
  • The MESOT-TREM-2012 results described were preliminary
  • Conventional radiological response criteria (WHO, RECIST) are difficult to apply to mesothelioma, and the modified criteria have been criticized for high inter-observer variability
  • No clinical studies had yet explored PD-1 or PD-L1 blocking agents in mesothelioma patients

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: Malignant Mesothelioma, Prognosis, Unresectable, Monoclonal, Clinical Trial.

Related studies

• Biomarkers for immune checkpoint inhibitors--authors' reply — L. Calabrò, M. Maio (2014)
• Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge — L. Calabrò, A. Morra, et al. (2018)
• Biomarkers for immune checkpoint inhibitors — L.A. Lievense, J.P. Hegmans, et al. (2014)
• CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy? — L. Calabrò, G.L. Ceresoli, et al. (2015)
• Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences — L. Calabrò, G.L. Ceresoli, et al. (2017)
• Targeting immune checkpoints: New opportunity for mesothelioma treatment? — E. Marcq, P. Pauwels, et al. (2015)

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