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

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 × 10 6 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.