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. 2025 Oct 24:e08754.
doi: 10.1002/advs.202508754. Online ahead of print.

Anti-PD-1 Nanobody-Armored MSLN CAR-T Therapy for Malignant Mesothelioma: Preclinical and Clinical Studies

Yan Sun  1   2 , Haochen Yang  3 , Qing Xu  4 , Xingya Li  5 , Jinxing Lou  1   2 , Jianchun Duan  6 , Jiachen Xu  6 , Zhuqing Liu  4 , Yong Xia  1   2 , Zhicai Lin  1   2 , Linlin Li  5 , Dan Sun  2 , Jiaguo Li  1   2 , Tao Liu  2 , Jun Guo  2 , Wenfeng Xu  2 , Weimin Zhu  2 , Yi Liu  2 , Boyang Sun  6 , Jia Zhong  6 , Lijie Rong  2 , Qijun Qian  1   2 , Chenqi Xu  3 , Jie Wang  6
Affiliations

Anti-PD-1 Nanobody-Armored MSLN CAR-T Therapy for Malignant Mesothelioma: Preclinical and Clinical Studies

Yan Sun et al. Adv Sci (Weinh). .

Abstract

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 × 106 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.

Keywords: CAR‐T; NAC‐T; first‐in‐human study; malignant mesothelioma.

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