Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

Our plain-English summary of Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma, by S.G. Gray (BMC Pulmonary Medicine, 2021).

The study

• Author: S.G. Gray
• Journal: BMC Pulmonary Medicine
• Published: 2021;21(1):148
• Type of article: Review
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The role of immunotherapy in cancer is now well-established, and therapeutic options such as checkpoint inhibitors are increasingly being approved in many cancers such as non-small cell lung cancer (NSCLC). Malignant pleural mesothelioma (MPM) is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Evidence from clinical trials of checkpoint inhibitors in this rare disease, suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer.

Main Text: While the majority of studies currently focus on the established checkpoint inhibitors (CTLA4 and PD1/PDL1), there are many other potential checkpoints that could also be targeted. In this review I provide a synopsis of current clinical trials of immunotherapies in MPM, explore potential candidate new avenues that may become future targets for immunotherapy and discuss aspects of immunotherapy that may affect the clinical outcomes of such therapies in this cancer.

Conclusions: The current situation regarding checkpoint inhibitors in the management of MPM whilst encouraging, despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Additional studies are therefore required to further delineate and improve our understanding of both checkpoint inhibitors and the immune system in MPM. Moreover, many new potential checkpoints have yet to be studied for their therapeutic potential in MPM. All these plus the existing checkpoint inhibitors will require the development of new biomarkers for patient stratification, response and also for predicting or monitoring the emergence of resistance to these agents in MPM patients. Other potential therapeutic avenues such CAR-T therapy or treatments like oncolytic viruses or agents that target the interferon pathway designed to recruit more immune cells to the tumor also hold great promise in this hard to treat cancer.

In plain English

This article was a review by a single author of immunotherapy for malignant pleural mesothelioma (MPM), a cancer the author described as associated with asbestos exposure. It summarized clinical trials of checkpoint inhibitor drugs given around surgery, as first treatment, and after earlier treatment, and discussed other approaches such as oncolytic viruses, CAR-T cells and dendritic cell vaccines. Among the trials described, Checkmate-743 led to US FDA approval of nivolumab plus ipilimumab as first treatment for unresectable MPM. That trial reported median survival of 18.1 months with the combination (95% CI, 16.8 to 21.5) versus 14.1 months with chemotherapy (95% CI, 12.5 to 16.2). Other trials had mixed results. A Dutch real-world program in patients with recurrent MPM reported median survival of only 6.7 months with nivolumab. The author also analyzed public gene-expression datasets. In those data, high LAG-3 expression was associated with better survival and high B7-H3 expression with worse survival. The author concluded that, despite durable responses, checkpoint inhibitors do not provide long-term benefit to most patients with cancer and that more studies are required.

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 clinical trials and research on immunotherapy in malignant pleural mesothelioma, with the author's own analysis of public gene-expression databases
• Who was studied: Published and ongoing clinical trials and studies of immunotherapy in malignant pleural mesothelioma. The author's own analysis used the Gordon MPM dataset (normal pleura versus malignant) via Oncomine and The Cancer Genome Atlas data via UALCAN.
• Exposure: Not an exposure study. The article reviewed immunotherapy treatments: checkpoint inhibitors such as nivolumab, ipilimumab, pembrolizumab, durvalumab and tremelimumab, as well as oncolytic viruses, CAR-T cells and dendritic cell vaccines. Asbestos was mentioned only as background, and no fiber types were named.
• Main results:
  • Analysis of the Checkmate-743 trial (reported by other researchers) led to FDA approval of nivolumab plus ipilimumab as first-line treatment for unresectable MPM.
  • In Checkmate-743, overall survival improved versus platinum-based standard chemotherapy (HR 0.74; 95% CI 0.61 to 0.89; P = .002). Median overall survival was 18.1 months with the combination (95% CI, 16.8 to 21.5) versus 14.1 months with chemotherapy (95% CI, 12.5 to 16.2). The 2-year survival rates were 41% and 27%.
  • In the Japanese MERIT trial (second-line nivolumab), overall survival was 17.3 months, which led to nivolumab's approval in Japan for salvage therapy in MPM.
  • Interim results of the CONFIRM phase III trial showed nivolumab superior to placebo for overall survival (hazard ratio 0.72, p = 0.018) and for progression-free survival (hazard ratio 0.61, p less than 0.001).
  • In the DETERMINE trial of tremelimumab versus placebo, median overall survival did not differ significantly between the groups (7.7 vs 7.3 months).
  • Data from the Dutch expanded access program suggested that, in a real-world setting, patients with recurrent MPM given nivolumab had a worse response rate and a median overall survival of 6.7 months.
  • In the author's analysis of TCGA data, high LAG-3 mRNA expression was associated with better overall survival.
  • In the author's analysis of TCGA data, high B7-H3 mRNA expression was associated with worse overall survival.
  • In Checkmate-743, PD-L1 status did not predict overall survival benefit.
  • The combined cost of ipilimumab plus nivolumab in the USA was estimated at approximately $153,800 for four cycles.
• The authors' conclusion: The author concluded that, despite durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer, and that additional studies are required.
• Limitations the authors state:
  • Results of the trials of immunotherapy given before surgery are not yet mature because the trials are still running.
  • The author described PD-L1 as a contentious biomarker, noting that some PD-L1-negative patients still respond to checkpoint inhibitors.

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: Immunotherapy, Pleural Mesothelioma, checkpoint inhibitors, Non-Small Cell Lung Cancer, Prognosis, Clinical Trial, Biomarker.

Related studies

• Is there a role for immunotherapy in malignant pleural mesothelioma? — A. Tartarone, R. Lerose, et al. (2018)
• Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance — K. Olino, T. Park, et al. (2020)
• Anti-CTLA-4 therapy for malignant mesothelioma — A. Guazzelli, E. Bakker, et al. (2017)
• Immunotherapy for Treatment of Pleural Mesothelioma: Current and Emerging Therapeutic Strategies — L. Chiec, D.S. Bruno (2024)
• Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations — W.J. Lesterhuis, C. Rinaldi, et al. (2015)
• Targeting immune checkpoints: New opportunity for mesothelioma treatment? — E. Marcq, P. Pauwels, et al. (2015)

Browse more research in BMC Pulmonary Medicine, or return to medical research.