Synapse - A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab

A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab Journal Article

Authors:	Adusumilli, P. S.; Zauderer, M. G.; Rivière, I.; Solomon, S. B.; Rusch, V. W.; O'Cearbhaill, R. E.; Zhu, A.; Cheema, W.; Chintala, N. K.; Halton, E.; Pineda, J.; Perez-Johnston, R.; Tan, K. S.; Daly, B.; Araujo Filho, J. A.; Ngai, D.; McGee, E.; Vincent, A.; Diamonte, C.; Sauter, J. L.; Modi, S.; Sikder, D.; Senechal, B.; Wang, X.; Travis, W. D.; Gönen, M.; Rudin, C. M.; Brentjens, R. J.; Jones, D. R.; Sadelain, M.
Article Title:	A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab
Abstract:	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.
Keywords:	cisplatin; antigen; immunotherapy; expression; overexpression; open-label; checkpoint blockade; coexpression
Journal Title:	Cancer Discovery
Volume:	11
Issue:	11
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2021-11-01
Start Page:	2748
End Page:	2763
Language:	English
ACCESSION:	WOS:000714626600015
DOI:	10.1158/2159-8290.Cd-21-0407
PROVIDER:	wos
PMCID:	PMC8563385
PUBMED:	34266984
Notes:	Article -- Source: Wos