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Immunotherapy approaches for malignant pleural mesothelioma

Abstract

Over the past decade, immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. In mesothelioma, a rare cancer with a dismal prognosis generally caused by exposure to asbestos, treatment with single or dual ICIs results in robust improvements in overall survival over previous standard-of-care therapies, both in the first-line and relapsed disease settings. Predictive biological features that underpin response to ICIs remain poorly understood; however, insights into the immune microenvironment and genomic landscape of mesothelioma as well as into their association with response or acquired resistance to ICIs are emerging. Several studies of rational combinations involving ICIs with either another ICI or a different agent are ongoing, with emerging evidence of synergistic antitumour activity. Non-ICI-based immunotherapies, such as peptide-based vaccines and mesothelin-targeted chimeric antigen receptor T cells, have demonstrated promising efficacy. Moreover, results from pivotal trials of dendritic cell vaccines and viral cytokine delivery, among others, are eagerly awaited. In this Review, we comprehensively summarize the key steps in the development of immunotherapies for mesothelioma, focusing on strategies that have led to randomized clinical evaluation and emerging predictors of response. We then forecast the future treatment opportunities that could arise from ongoing research.

Key points

  • Immunotherapy has emerged as an effective treatment modality for mesothelioma during the last decade.

  • First-line combination immunotherapy with ipilimumab and nivolumab is the first new standard of care approved for patients since 2004.

  • Chemoimmunotherapy is emerging as a next step in the evolution of mesothelioma therapy with results from three pivotal phase III trials in the frontline setting awaited.

  • Factors determining response to immunotherapy remain elusive; however, detailed response correlations with genomic, transcriptomic and immune landscape features are emerging.

  • Although immune-checkpoint inhibition has been the most successful approach to date, emerging strategies, including dendritic cell vaccination and adenoviral cytokine delivery, are promising strategies in ongoing late-stage clinical trials.

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Fig. 1: Timeline of clinical trials of immunotherapies in MPM.
Fig. 2: Immunotherapy combination strategies currently under clinical investigation.

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All the authors contributed equally to all aspects of the article.

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D.A.F. has received grants from Astex Therapeutics, Bayer, Boehringer Ingelheim and MSD; personal fees from Aldeyra, Inventiva, Paredox and Roche; and non-financial support (involving the provision of study drugs) from Bergen Bio, BMS, Clovis Oncology, Eli Lilly, Pierre Fabre and Roche. The other authors declare no competing interests.

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Fennell, D.A., Dulloo, S. & Harber, J. Immunotherapy approaches for malignant pleural mesothelioma. Nat Rev Clin Oncol 19, 573–584 (2022). https://doi.org/10.1038/s41571-022-00649-7

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