Issues

Cancers within the pleural cavity such as malignant pleural mesothelioma (MPM) are aggressive and typically have poor response to therapies. Immune checkpoint inhibitors have been indicated for second-line use in this disease; however, low expression of PD-L1 has contributed to poor response in patients given monotherapy. Chimeric antigen receptor (CAR) T cells developed to target mesothelin and be delivered to the pleural cavity have shown promise in mouse models, but PD-1/PD-L1 signaling promoted functional exhaustion of these CAR T cells; administration of an anti–PD-1 therapy abrogated this effect. Adusumilli and colleagues therefore conducted a first-in-human phase I clinical trial combining pembrolizumab with intrapleural administration of CAR T cells targeting mesothelin. This trial indicated that this combination was not only feasible and safe but had antitumor efficacy, with two patients with MPM experiencing complete metabolic responses, and persistence of functional CAR T cells was observed. For more information, see the article by Adusumilli and colleagues on page 2748.