Targeting Mesothelin with Modified T Cells

According to preliminary data from a small phase I study, using chimeric antigen receptor (CAR) T cells to target mesothelin in solid tumors is both feasible and safe. The results were reported by Janos Tanyi, MD, PhD, a gynecologic oncologist at the University of Pennsylvania School of Medicine, at the American Association for Cancer Research Annual Meeting 2015 in Philadelphia, PA, April 18–22.

CAR T-cell therapy involves genetically engineering a patient's T cells to recognize and destroy specific antigens on tumor cells—in this case, mesothelin, which is present in a range of tumor types, including gastric and esophageal cancers. Tanyi and his colleagues had previously delivered CAR-encoding DNA to T cells through electroporation, which uses brief electrical pulses to increase cell permeability. However, “CAR expression was very short-lived, with limited antitumor effects,” he said, “and patients required multiple infusions to maintain even those transient CAR levels.”

In this study, the researchers used a lentivirus as their delivery method; this integrated the DNA into the T cells' genome and generated long-term, stable CAR expression. Six patients were enrolled in the first cohort, two each with epithelial mesothelioma, ovarian carcinoma, and pancreatic adenocarcinoma. All had advanced disease and had undergone at least one surgery and multiple rounds of chemotherapy. The patients' T cells were collected by apheresis and engineered to produce mesothelin-targeting CARs; each patient then received a single low-dose intravenous infusion of their genetically altered T cells.

“These modified T cells successfully infiltrated the patients' tumors and persisted for up to 28 days in the blood,” Tanyi said—considerably longer than the detection period of 1 to 2 days seen with electroporation, he noted. Three patients experienced grade 3 adverse events that included rash, fatigue, and hypotension; however, there were no life-threatening immune side effects such as cytokine release syndrome or macrophage activation syndrome, and the therapy was generally well tolerated.

In addition, four patients achieved stable disease within 28 days, Tanyi added, suggesting that this approach has some antitumor efficacy. While the CAR T cells also found their way to normal tissue expressing mesothelin, no associated toxicities were observed.

“Though early, these are encouraging data that give us cautious optimism for the future of CAR T-cell therapy in solid tumors,” said Michel Sadelain, MD, PhD, director of the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY. He suggested exploring different delivery routes such as injecting CAR T cells into the pleural cavity, and that equipping CAR T cells with a suicide gene—to ensure their self-destruction, should severe side effects occur—could be beneficial.

The Penn researchers will expand their study to four cohorts, recruiting 15 to 24 patients in total; separate investigations of mesothelin-targeting CAR T-cell therapy are also under way at MSKCC and the NCI. The long-term goal, Tanyi noted, is to refine this immunotherapeutic approach and develop CAR T cells that can persist for years, not just weeks or months, “so besides eliminating cancer cells, they can prevent recurrence.”