Anti‐PD‐1 Nanobody‐Armored MSLN CAR‐T Therapy for Malignant Mesothelioma: Preclinical and Clinical Studies
Malignant mesothelioma (MM) is an aggressive and currently incurable cancer with limited therapeutic options. Due to the high expression of mesothelin in this cancer, anti-PD-1 nanobody-armored mesothelin-targeting CAR-T (NAC-T) cells are developed. Based on the enhanced anti-tumor activity observed in preclinical in vitro and in vivo studies, a first-in-human clinical trial is initiated. Eleven patients with malignant mesothelioma who have progressed after standard therapies receive intravenous infusions of 5-20 × 10<sup>6</sup> per kg NAC-T cells following lymphodepletion. The treatment is well tolerated, with no dose-limiting toxicity observed. The overall response rate is 63.6%, including one complete response, and the disease control rate is 100%. The median progression-free survival is 5.0 months, and the median overall survival is 25.6 months. Moreover, T cell receptor and single-cell sequencing analyses in patients with varying responses revealed specific clonal expansion of T cell subtypes and enhanced reactivity to tumor-associated antigens. These findings suggest that NAC-T cell therapy represents a promising therapeutic strategy for patients with malignant mesothelioma.
Authors
- Dan Sun (ORCID: https://orcid.org/0000-0001-6148-2769)
- Chenqi Xu (ORCID: https://orcid.org/0000-0002-4968-6782)
- Jun Guo (ORCID: https://orcid.org/0000-0002-6980-9700)
- Jinxing Lou
- Wenfeng Xu (ORCID: https://orcid.org/0000-0002-1313-9189)
- Yong Xia (ORCID: https://orcid.org/0000-0002-4726-6290)
- Weimin Zhu (ORCID: https://orcid.org/0000-0002-2420-0731)
- Haochen Yang (ORCID: https://orcid.org/0000-0003-4273-5411)
- Jiachen Xu (ORCID: https://orcid.org/0000-0003-4565-6364)
- Jianchun Duan (ORCID: https://orcid.org/0000-0003-1479-2304)
- Lijie Rong (ORCID: https://orcid.org/0000-0001-6141-9575)
- Qijun Qian (ORCID: https://orcid.org/0000-0002-3285-5009)
- Yi Liu (ORCID: https://orcid.org/0000-0002-3954-6102)
- Tao Liu (ORCID: https://orcid.org/0000-0001-7455-8240)
- Lin Li (ORCID: https://orcid.org/0000-0002-8014-8296)
- Jie Wang (ORCID: https://orcid.org/0000-0002-5602-0487)
- Yan Sun (ORCID: https://orcid.org/0000-0003-2065-0070)
- Zhuqing Liu (ORCID: https://orcid.org/0000-0003-3852-8807)
- XingYa Li
- Qing Xu (ORCID: https://orcid.org/0000-0002-4785-2994)
- Jiaguo Li (ORCID: https://orcid.org/0009-0004-0131-1596)
- Boyang Sun (ORCID: https://orcid.org/0000-0001-6334-5258)
- Zhicai Lin
- Jia Zhong
Institutions
- Tongji University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Shanghai Cancer Institute (CN)
- Center for Excellence in Molecular Cell Science (CN)
- Shanghai Tenth People's Hospital (CN)
- Shanghai Cell Therapy Research Institute (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1002/advs.202508754
- Citations
- 2
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.09