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

Our plain-English summary of Anti-PD-1 Nanobody-Armored MSLN CAR-T Therapy for Malignant Mesothelioma: Preclinical and Clinical Studies, by Y. Sun, H. Yang, Q. Xu, et al (Advanced Science, 2026).

The study

• Authors: Y. Sun, H. Yang, Q. Xu, X. Li, J. Lou, J. Duan, J. Xu, Z. Liu, Y. Xia, Z. Lin, L. Li, D. Sun, J. Li, T. Liu, J. Guo, W. Xu, W. Zhu, Y. Liu, B. Sun, J. Zhong, L. Rong, Q. Qian, C. Xu, J. Wang
• Journal: Advanced Science
• Published: 2026;13(35):e08754
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

In plain English

This article reported laboratory and animal experiments followed by a first-in-human phase I, open-label, single-arm, multicentre, investigator-initiated trial of mesothelin (MSLN)-targeting CAR-T cells armed with a self-secreted alpaca-derived anti-PD-1 nanobody (NAC-T). In culture, NAC-T cells kept surface PD-1 blocked and expanded more than non-armoured MSLN CAR-T cells; in mice bearing NCI-H226 human mesothelioma xenografts, tumour volume at day 28 was 242.67 plus or minus 26.66 mm3 with NAC-T versus 547.17 plus or minus 69.10 mm3 with MSLN CAR-T. Eleven heavily pretreated patients with malignant mesothelioma received intravenous NAC-T at 5, 10, 15 or 20 million cells per kg after lymphodepletion. No dose-limiting toxicity occurred; cytokine release syndrome affected 8 of 11 (73%), all below grade 3. The overall response rate was 63.6% (7/11), with one complete response, six partial responses and four with stable disease (disease control 100%); median progression-free survival was 5.0 months (95% CI, 3.0 to 9.0) and median overall survival 25.6 months (95% CI, 7.7 to not reached). The authors described the therapy as promising.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical in vitro and mouse xenograft experiments followed by a first-in-human phase I dose-escalation clinical trial (two cohorts)
• Who was studied: 11 patients with malignant mesothelioma (6 in cohort 1 enrolled September 2020 to November 2022; 5 in cohort 2 enrolled January to September 2022) at centres in Shanghai and Beijing, China; plus NOG mice bearing NCI-H226 human mesothelioma xenografts
• Exposure: Intravenous infusion of anti-PD-1 nanobody-armoured MSLN CAR-T (NAC-T) cells at four dose levels (5, 10, 15, 20 million cells per kg) after cyclophosphamide/fludarabine lymphodepletion; four patients received a second infusion
• Main results:
  • Among all 11 treated patients: overall response rate 63.6% (7/11), one complete response, six partial responses, four stable disease, disease control rate 100% (11/11)
  • Survival for all 11 patients: median progression-free survival 5.0 months (95% CI, 3.0–9.0); median overall survival 25.6 months (95% CI, 7.7 – not reached)
  • Safety in the 11 treated patients: no dose-limiting toxicity at any dose level; cytokine release syndrome in 8 of 11 (73%), 5 of 6 in cohort 1 and 3 of 5 in cohort 2, all below grade 3
  • Response rate was higher in patients with malignant peritoneal mesothelioma than pleural mesothelioma (83.3% vs 40.0%), which the authors state was not statistically significant (6 vs 5 cases, p = 0.24)
  • In mice bearing 300 mm3 NCI-H226 tumours, tumour volume at day 28 after infusion was smaller in the NAC-T group than the MSLN CAR-T group
• The authors' conclusion: The authors concluded that NAC-T therapy showed promising anti-tumour activity and favourable tolerability in patients with malignant mesothelioma
• Limitations the authors state:
  • The patient cohort was limited, making estimation of the immunogenicity of NAC-T cells difficult
  • Nanobody secretion depends on T-cell activation, which may vary between patients and is hard to standardise
  • Mechanistic analyses used bulk peripheral T cells because few NAC-T cells were detectable in blood
  • No head-to-head comparison with CAR-T plus systemic immune checkpoint inhibitor

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelin, Clinical Trial, Progression-Free Survival, Median Overall Survival.

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