Targeting immune checkpoints: New opportunity for mesothelioma treatment?

Our plain-English summary of Targeting immune checkpoints: New opportunity for mesothelioma treatment?, by E. Marcq, P. Pauwels, J.P. van Meerbeeck, et al (Cancer Treatment Reviews, 2015).

The study

• Authors: E. Marcq, P. Pauwels, J.P. van Meerbeeck, E.L. Smits
• Journal: Cancer Treatment Reviews
• Published: 2015;41(10):914-24
• Type of article: Review
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma is an aggressive cancer linked to asbestos exposure in most patients. Due to the long latency between exposure and presentation, incidence is expected to further increase in the next decade, despite the ban on asbestos import which occurred at the end of last century in industrialized countries. Platinum-based palliative chemotherapy is the only treatment with proven benefit on outcome, resulting in selected patients in a median overall survival of about 1 year. Therefore, there is room for therapeutic improvement using a new strategy to prolong survival. Dealing with cancer cell induced immunosuppression is a promising approach. Reactivating immune responses that are silenced by immune checkpoints recently gained a lot of interest. Checkpoint blockade has already shown promising preclinical and clinical results in several cancer types and is currently also being investigated in mesothelioma. Here, we discuss the expression patterns and mechanisms of action of CTLA-4 and PD-1 as the two most studied and of TIM-3 and LAG-3 as two interesting upcoming immune checkpoints. Furthermore, we review the clinical results of molecules blocking these immune checkpoints and point out their future opportunities with a special focus on mesothelioma.

Copyright © 2015 Elsevier Ltd. All rights reserved.

In plain English

This article was a review, not an original study. The authors described how four 'immune checkpoint' molecules (CTLA-4, PD-1, TIM-3 and LAG-3) hold back the immune system. They reviewed drugs blocking them, mainly CTLA-4 and PD-1, across several cancers, with a special focus on malignant pleural mesothelioma; no clinical-grade TIM-3 antibodies were yet being tested. It states this cancer is linked to asbestos exposure in most patients but did not study asbestos. In an earlier phase II tremelimumab trial in patients with chemotherapy-resistant advanced disease, disease control was seen in 31% and median overall survival was 10.7 months. A later tremelimumab study of 29 patients reported median overall survival of 11.3 months. Preliminary results of a pembrolizumab trial in 25 patients reported partial responses in 7 (28%) and stable disease in 12 (48%). The reviewed studies found PD-L1 in 20% to 70% of mesothelioma samples. The authors concluded that PD-1 and PD-L1 blocking antibodies might be a good approach for mesothelioma treatment. They noted that few studies had focused on this cancer and that whether PD-L1 predicts response was unknown.

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 laboratory, animal and clinical research on immune checkpoint blocking drugs, with a special focus on mesothelioma
• Who was studied: No study population of its own. The authors reviewed published studies, conference reports and clinical trials registered on ClinicalTrials.gov (listed as of 09/09/2015), including trials open to mesothelioma patients.
• Exposure: Asbestos exposure was not studied. The article mentions it only as background, stating that malignant pleural mesothelioma is linked to asbestos exposure in most patients. The subject of the review was antibody drugs blocking CTLA-4 (ipilimumab, tremelimumab), PD-1 (nivolumab, pembrolizumab, pidilizumab), PD-L1, PD-L2, LAG-3 and TIM-3. The clinical review focused mainly on CTLA-4 and PD-1, and no clinical-grade TIM-3 antibodies were yet being tested.
• Main results:
  • From an earlier phase II trial (Calabrò et al., 2013) of tremelimumab in patients with chemotherapy-resistant advanced malignant pleural mesothelioma: disease control was noted in 31% of patients.
  • In the same trial, median overall survival was 10.7 months. The review compared this with 8.7 months reported in a separate retrospective review of second-line chemotherapy.
  • In the later MESOT-TREM-2012 study of tremelimumab (29 patients enrolled), the drug showed an acceptable safety profile and a median overall survival of 11.3 months.
  • Preliminary data from the phase I KEYNOTE-028 trial of pembrolizumab in 25 malignant pleural mesothelioma patients: partial responses in 7 patients (28%), stable disease in 12 patients (48%), and an overall disease control rate of 76%.
  • Across the studies reviewed, PD-L1 expression measured by immunohistochemistry in malignant pleural mesothelioma samples ranged between 20% and 70%.
  • In the studies reviewed, PD-L1 expression was significantly associated with worse survival, and overexpression was more common in non-epithelioid tumors.
  • Results of a randomized phase II double-blind trial comparing tremelimumab with placebo in unresectable mesothelioma were still awaited.
  • No clinical-grade antibodies targeting TIM-3 were yet being tested.
  • Nothing had been described in mesothelioma patients about PD-L2, LAG-3 or TIM-3 at the time of the review.
• The authors' conclusion: The authors concluded that, taken together, the results show PD-1 and PD-L1 blocking antibodies might be a good approach for malignant pleural mesothelioma treatment. They wrote that encouraging CTLA-4 data and PD-1/PD-L1 expression data support further investigation.
• Limitations the authors state:
  • The authors noted that only a few studies had so far focused on mesothelioma.
  • The authors stated it was unknown whether PD-L1 is a conclusive biomarker for predicting response to PD-1 or PD-L1 targeted treatment, and that PD-L1 expression can vary over time.
  • The authors described current data on the role of tumor-infiltrating lymphocytes in malignant pleural mesothelioma as controversial.
  • The authors noted that nothing had yet been described about combining chemotherapy with immune checkpoint blockade 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: Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Latency, Palliative Care, Chemotherapy, Median Overall Survival, CTLA-4.

Related studies

• Anti-CTLA-4 therapy for malignant mesothelioma — A. Guazzelli, E. Bakker, et al. (2017)
• Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences — L. Calabrò, G.L. Ceresoli, et al. (2017)
• Immune checkpoint blockade in malignant mesothelioma — L. Calabrò, M. Maio (2015)
• Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas — C. Combaz-Lair, F. Galateau-Sallé, et al. (2016)
• Downregulation of the PD-1/PD-Ls pathway in peripheral cells correlates with asbestosis severity — M. Qiu, Y. Chen, et al. (2021)
• Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge — L. Calabrò, A. Morra, et al. (2018)

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