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

Area of Science:

• Oncology
• Immunotherapy
• Cellular Therapy

Background:

• Malignant mesothelioma (MM) is an aggressive cancer with limited treatment options.
• Mesothelin is highly expressed on MM cells, making it a viable therapeutic target.
• Existing therapies for MM offer limited efficacy, necessitating novel treatment strategies.

Purpose of the Study:

• To evaluate the safety and efficacy of anti-PD-1 nanobody-armored mesothelin-targeting CAR-T (NAC-T) cells in patients with malignant mesothelioma.
• To assess the anti-tumor activity and clinical outcomes of NAC-T cell therapy in a first-in-human clinical trial.

Main Methods:

• A first-in-human clinical trial was conducted involving eleven patients with advanced malignant mesothelioma.
• Patients received intravenous infusions of NAC-T cells at doses ranging from 5-20 × 10^6 cells/kg following lymphodepletion.
• T cell receptor and single-cell sequencing analyses were performed to investigate treatment responses.

Main Results:

• NAC-T cell therapy was well-tolerated, with no dose-limiting toxicity observed.
• The overall response rate was 63.6% (including one complete response), and the disease control rate was 100%.
• Median progression-free survival was 5.0 months, and median overall survival was 25.6 months. Sequencing revealed enhanced T cell reactivity.

Conclusions:

• NAC-T cell therapy demonstrates a favorable safety profile and significant clinical efficacy in malignant mesothelioma.
• The findings suggest that NAC-T cell therapy is a promising new treatment strategy for patients with malignant mesothelioma.
• Further investigation into the mechanisms of T cell expansion and reactivity could optimize this therapy.