Malignant mesothelioma is a treatment-resistant type of cancer that starts in the mesothelial lining of the pleura or the abdominal cavity. Patients with this disease have poor prognosis and very limited treatment options. A recent article in Biomarker Research discussed clinical trials examining the safety and potential of chimeric antigen receptor (CAR) T-cell therapy to fight malignant mesothelioma.
“The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in malignant mesothelioma, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of malignant mesothelioma patients and not (or very modestly) present in healthy tissues,” wrote the authors, led by Laura Castelletti of the Li Ka Shing Cell and Gene Therapy Program at the University of Sydney in Australia. In addition, “its expression at high levels has been associated with increased aggressiveness and invasiveness.”
Clinical trials have explored anti-MSLN CAR T-cell therapy in malignant mesothelioma. Most have been phase I/II studies using safety as the primary endpoint. The studies demonstrated only low-grade adverse effects, but response rates have were low.
The authors pustulated two possible reasons for the limited efficacy. First, because efficacy testing was not the primary endpoint of the studies, CAR T cell dosage must be optimized. Second, the limited efficacy may be related to the immunosuppressive tumor microenvironment, which may reduce infiltration, efficacy and persistence.
Therefore, current studies at the University of Pennsylvania, Memorial Sloane Kettering Cancer Center, MaxCyte and institutions in China are examining specific methods to overcome those challenges, such as:
- local (intra-tumor) delivery of anti-MSLN CAR T cells
- improved CAR design and co-stimulation
- attempts to avoid T-cell exhaustion
- combination therapies with checkpoint inhibitors and oncolytic viruses
“It is too early to determine which anti-MSLN CAR T-cell approach works best against malignant mesothelioma,” the authors concluded. “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 malignant mesothelioma patients.”