Developing immunotherapies for mesothelioma 

Immunogenicity of mesothelioma has been investigated over the years. This disease is characterized by a low mutational burden and an immunosuppressive tumor microenvironment enriched by exhausted and regulatory T cells and type M2-machrophages (Front Oncol. 2021 Jun 23;11:660039). Several immunotherapeutic approaches have been developed therefore to treat this disease. With the use of immune-checkpoints inhibitors in the further-line settings for patients with mesothelioma, improvement of survival compared to historical data were reported. This finding supported the further use of immune checkpoint inhibitors alone or in combination with chemotherapies in the first line settings.

In 2020, data of the CheckMATE 743 trial changed the way patients with mesothelioma are treated and 3-year overall survival (OS) data were presented this year at the ESMO Congress 2021 showing the longer survival for patients receiving Nivolumab/Ipilimumab compared with standard chemotherapy. Further phase II trials included patients with mesothelioma to be treated with the combination of standard chemotherapy and durvalumab with promising results (Lancet Oncol. 2020 Sep;21(9):1213-1223; Nat Med. 2021 Nov;27(11):1910-1920). However, the efficacy of these approaches warrants further investigation. Despite the encouraging and positive results, the majority of patients will not respond to treatment at the start or during the course of treatment.  New therapies are needed and several combinations are now under investigations including with chemotherapies and other immunomodulatory agents. Another approach currently explored is the use of cellular therapies for mesothelioma. Recently, safety data were reported for the use of CAR T cells targeting mesothelin (Cancer Discov. 2016 Feb;6(2):133-46) and FAP (Ann Oncol. 2021 Jan;32(1):120-121). At the ESMO Congress 2021, data on safety and efficacy with the use of T cells transduced with a modified T-cell-receptor targeting mesothelin were also reported.

At the ESMO Immuno-Oncology Congress 2021, new ways to improve the use of CAR T cells targeting mesothelin are now presented (Abstract 46MO) and based on these findings a phase I trial is ongoing. Along with treatments with immune checkpoint inhibitors and cellular therapies, other immunotherapies are investigated. All these approaches will enable researchers to understand the way to make the treatment of mesothelioma more efficacious through immunomodulation and tumour targeting, and the combination of different approaches will hopefully allow the long-term improvement of patients’ survival.