… Malignant pleural mesothelioma is an aggressive solid tumor that arises either as a primary tumor or as metastatic disease secondary to lung or breast cancer. The disease has a poor prognosis, and the FDA has not approved a new treatment for malignant pleural mesothelioma since 2003, Adusumilli noted.
The disease responds poorly to immune checkpoint inhibition, which is associated with a median progression-free survival (PFS) of 4 to 5.6 months. The National Comprehensive Cancer Network included anti–PD-1 therapy as an option for second-line treatment of malignant pleural mesothelioma.
Adusumilli and colleagues previously demonstrated that mesothelin, a cell-surface antigen, is highly expressed in malignant pleural disease and is associated with an aggressive clinical course and poor survival. Normal tissues have only low-level expression of mesothelin.
Investigators developed fully human mesothelin-targeted CARs, incorporating the inducible caspase-9 safety switch that can be activated to neutralize CAR T cells in the event of unexpected toxicity. In preclinical studies, intrapleural administration of the CAR T cells demonstrated antitumor activity. The studies also showed that CAR T cells can become functionally exhausted in the presence of a large tumor burden, but administration of an anti–PD-1 agent can revive CAR T-cell function. [footnotes omitted]