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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
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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. See related commentary by Aldea et al., p. 2674. This article is highlighted in the In This Issue feature, p. 2659
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“The results of phase 1 study demonstrated CAR-T cell therapy combined with α-PD-1/PD-L1 had confirmed antitumor activity in patients with malignant pleural diseases [344].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [344]
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Metadata
- 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.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- 6Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
- 5Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
- Corresponding author
- Adusumilli, Prasad S.
- ORCID
- Adusumilli, Prasad S.
- Zauderer, Marjorie G.
- Rivière, Isabelle
- Solomon, Stephen B.
- Rusch, Valerie W.
- O'Cearbhaill, Roisin E.
- Cheema, Waseem
- Chintala, Navin K.
- Pineda, John
- Perez-Johnston, Rocio
- Tan, Kay See
- Daly, Bobby
- Sauter, Jennifer L.
- Modi, Shanu
- Wang, Xiuyan
- Travis, William D.
- Gönen, Mithat
- Rudin, Charles M.
- Brentjens, Renier J.
- Jones, David R.
- Sadelain, Michel
- Venue
- Cancer Discovery
- Published
- 2021-07-15
- Volume
- 11
- Issue
- 11
- Pages
- 2748-2763
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8563385
- OpenAlex
- W3179214161
- Cited by
- 605
- References
- 37
- Citations by year
- 2026: 124 · 2025: 119 · 2024: 131 · 2023: 125 · 2022: 90 · 2021: 15
- FWCI
- 32.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P30 CA008748, R01 CA236615-01, R01 CA235667)
- U.S. Department of Defense (BC132124, LC160212, CA180889)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Keywords
- mesothelin, chimeric antigen receptor T cells, CAR T-cell therapy, malignant pleural mesothelioma, malignant pleural effusion, pembrolizumab, anti-PD-1 therapy, intrapleural administration, combination immunotherapy, autologous T cells, safety and tolerability, overall survival
- MeSH terms
- Mesothelin, Humans, Mesothelioma, Pleural Diseases, Immunotherapy, Adoptive, Antibodies, Monoclonal, Humanized
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