Optimising response to immunotherapies in pleural mesothelioma: clinical data and alternative models for the evaluation of new strategies

BACKGROUND: Pleural mesothelioma (PM) is a rare tumour, usually associated with previous asbestos exposure. Standard frontline, pemetrexed/platinum-based chemotherapy has been challenged since 2020 by dual immunotherapy, that is, anti-programmed cell death-1 (anti-PD-1) + anti-cytotoxic T lymphocyte-associated antigen-4 immune checkpoint inhibitors and recently by combination of chemotherapy + anti-PD-1. However, PM prognosis remains globally poor, without validated curative treatment to date. METHODS: We reviewed alternative pre-clinical models and clinical data for the evaluation of new treatments and strategies to optimize response to immunotherapies in pleural mesothelioma. RESULTS: Various innovative immunotherapies alone or combined with standard treatments and/or targeted therapies are currently assessed by clinical trials. The evaluation of these new strategies deserves relevant preclinical models, requiring the use of human models in addition to or even instead of mouse models. These models recapitulate, at least partially, heterogeneity of the tumours and offer new perspectives for the development and evaluation of immunotherapies. However, like all models, they exhibit advantages and disadvantages needing to be identified in order to use them to answer a well-defined biological question. CONCLUSIONS: Along with ongoing trials testing innovative immunotherapies and strategies in pleural mesothelioma, original pre-clinical models are required to optimize these strategies and discover new ones for our patients.