Success of Checkpoint Blockade Paves the Way for Novel Immune Therapy in Malignant Pleural Mesothelioma

Our plain-English summary of Success of Checkpoint Blockade Paves the Way for Novel Immune Therapy in Malignant Pleural Mesothelioma, by L. Rondon, R. Fu, M.R. Patel (Cancers, 2023).

The study

• Authors: L. Rondon, R. Fu, M.R. Patel
• Journal: Cancers
• Published: 2023;15(11)
• Type of article: Review
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a malignancy associated with asbestos exposure and is typically categorized as an orphan disease. Recent developments in immunotherapy with anti-PD-1 and anti-CTLA-4 antibodies, specifically with agents nivolumab and ipilimumab, have demonstrated an improvement in overall survival over the previous standard chemotherapy leading to their FDA-approval as first-line therapy for unresectable disease. For quite some time, it has been known that these proteins are not the only ones that function as immune checkpoints in human biology, and the hypothesis that MPM is an immunogenic disease has led to an expanding number of studies investigating alternative checkpoint inhibitors and novel immunotherapy for this malignancy. Early trials are also supporting the notion that therapies that target biological molecules on T cells, cancer cells, or that trigger the antitumor activity of other immune cells may represent the future of MPM treatment. Moreover, mesothelin-targeted therapies are thriving in the field, with forthcoming results from multiple trials signaling an improvement in overall survival when combined with other immunotherapy agents. The following manuscript will review the current state of immune therapy for MPM, explore the knowledge gaps in the field, and discuss ongoing novel immunotherapeutic research in early clinical trials.

In plain English

This article is a narrative review, not new research. The authors described trials of immune treatments for malignant pleural mesothelioma, which they called strongly linked to asbestos exposure. They did not explain how they chose the trials. In the reviewed CheckMate 743 trial, median overall survival was 18.1 months (95% confidence interval 16.8 to 21.4) with nivolumab plus ipilimumab versus 14.1 months (12.4 to 16.2) with standard chemotherapy. This led to FDA approval for previously untreated, unresectable disease, the authors noted. In CONFIRM, median overall survival was 10.2 months with nivolumab versus 6.9 months with placebo. Two other reviewed trials, DETERMINE (tremelimumab) and PROMISE-MESO (pembrolizumab), did not show longer survival. They also described trials of mesothelin-targeted and dendritic cell treatments, and mostly early or preclinical work on B7-H3-targeted treatments and cancer-killing viruses. No trials yet directly used natural killer cells for this cancer, they noted. Too few patients with non-epithelioid tumors were enrolled to reach a consensus about them, they noted. The authors concluded that small trials and selection bias leave outcomes uncertain, but the field holds promise.

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 published and ongoing clinical trials of immunotherapy for malignant pleural mesothelioma. No search method or selection criteria are described.
• Who was studied: No patients were studied directly. The review covered clinical trials of patients with malignant pleural mesothelioma (MPM), including checkpoint inhibitor trials and ongoing trials of novel immunotherapies.
• Exposure: Asbestos was not studied; asbestos exposure is mentioned only as the background cause of MPM. The treatments reviewed were:
• anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies (nivolumab, ipilimumab, pembrolizumab, tremelimumab, durvalumab and others)
• mesothelin-targeted therapies
• B7-H3-targeted therapies
• NK cell, dendritic cell and oncolytic virus approaches
• Main results:
  • CheckMate 743 trial (reviewed, not conducted by the authors):
• Nivolumab plus ipilimumab: median overall survival 18.1 months (95% CI 16.8 to 21.4).
• Platinum plus pemetrexed chemotherapy: 14.1 months (12.4 to 16.2).
• Hazard ratio 0.74 (96.6% CI 0.60 to 0.91).
  The review states this led to FDA approval for previously untreated, unresectable MPM.
  • CONFIRM trial (332 patients, mostly treated in the third-line setting): median overall survival was 10.2 months with nivolumab and 6.9 months with placebo (adjusted HR 0.69, 95% CI 0.52 to 0.91).
  • DETERMINE trial: tremelimumab did not prolong overall survival compared with placebo (7.7 months vs 7.3 months, HR 0.92, 95% CI 0.76 to 1.12).
  • PROMISE-MESO trial (144 previously treated patients): compared with chemotherapy, pembrolizumab did not give longer progression-free survival (2.5 vs 3.4 months) or overall survival (10.7 vs 11.7 months).
  • MAPS 2 trial: the 12-week disease control rate was 40% with nivolumab alone and 52% with nivolumab plus ipilimumab.
  • Phase I trial of regionally delivered mesothelin-targeted CAR-T cells combined with pembrolizumab: the objective response rate was 12.5%.
  • The authors state that there were no trials directly using a natural killer cell strategy for MPM. Their discussion of NK cells rests on preclinical work.
• The authors' conclusion: The authors concluded that small sample sizes and selection bias in mesothelioma trials leave uncertainty about treatment outcomes, but that the field holds promise for potential breakthroughs.
• Limitations the authors state:
  • The authors state that the reviewed trials enrolled too few patients with non-epithelioid histology to reach a consensus about treatment response by histology.
  • The authors state that predictive biomarkers for checkpoint inhibitor response have not been identified, and that the predictive value of PD-L1 testing for survival needs more study.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Immunotherapy, CTLA-4, Nivolumab (Opdivo), Ipilimumab (Yervoy), Overall Survival, Chemotherapy.

Related studies

• Combination immune checkpoint blockade as an effective therapy for mesothelioma — V.S. Fear, C. Tilsed, et al. (2018)
• Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge — L. Calabrò, A. Morra, et al. (2018)
• Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC — F. Facchinetti, A. Marabelle, et al. (2016)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)
• Recent Advances of Immune Checkpoint Inhibition and Potential for (Combined) TIGIT Blockade as a New Strategy for Malignant Pleural Mesothelioma — S. Rovers, A. Janssens, et al. (2022)
• Immune checkpoint blockade in malignant mesothelioma — L. Calabrò, M. Maio (2015)

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