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 × 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.