Abstract
Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.
Introduction
Malignant mesothelioma (MM) is an aggressive, treatment-resistant and relatively rare cancer affecting the mesothelial lining of the pleura or abdominal cavity, often elicited by prior asbestos exposure. There are three histological subtypes of MM: epithelioid, sarcomatoid and biphasic. The epithelioid form of MM is the most common subtype and has a better prognosis than the biphasic and sarcomatoid types. MM has shown resistance against traditional oncological therapies and one of the lowest survival rates of any cancer type. Novel immunotherapeutic approaches targeting the tumor-associated antigen (TAA) mesothelin (MSLN) are currently being tested in clinical trials and have the potential to improve survival rates and prognosis in MM, especially anti-MSLN Chimeric Antigen Receptor (CAR) T cell therapy, which is the focus of this review.
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