Journal
CANCER DISCOVERY
Volume 11, Issue 11, Pages 2748-2763Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0407
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Funding
- NIH [P30 CA008748, R01 CA236615-01, R01 CA235667]
- U.S. Department of Defense [BC132124, LC160212, CA170630, CA180889]
- Baker Street Foundation
- Batishwa Fellowship
- Comedy vs. Cancer Award
- Derfner Foundation
- Dalle Pezze Foundation
- Esophageal Cancer Education Fund
- Geoffrey Beene Foundation
- Memorial Sloan Kettering Technology Development Fund
- Miner Fund for Mesothelioma Research
- Commonwealth Foundation for Cancer Research
- Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center
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Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is safe, feasible, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.
Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for >= 6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors. SIGNIFICANCE: Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.
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