Mesothelin-Targeting Armoured CAR-T Cells for Malignant Pleural Mesothelioma
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Embargo End Date
2025-08-06
ICR Authors
Authors
Hawkins, E
Document Type
Thesis or Dissertation
Date
2025-02-06
Date Accepted
Abstract
Second and third generation chimeric antigen receptor (CAR)-T cells have shown significant clinical benefit in haematological malignancies, which has not yet been observed in solid tumours. Malignant pleural mesothelioma (MPM) is a highly aggressive tumour with limited treatment options and poor patient prognosis, largely attributed to the tumour-specific tumour microenvironment (TME). In these highly immunosuppressive tumours, mesothelin-targeting CAR-T cells (M11-CAR-T cells) have shown limited clinical benefit so far.
Previously, combining M11-CAR-T cells with an anti-transforming growth factor-β (TGF-β) antibody has augmented their effect preclinically, owing to inhibition of immunosuppressive functions of TGF-β in the TME. This project aims to develop a CAR-T cell therapy for MPM, using the M11-CAR with downstream secretion of TGF-β inhibitory peptides (M11-β-CAR), ultimately aiming to augment M11-CAR-T cell efficacy in the context of MPM.
To test this, M11-β-CAR constructs were cloned and assessed in vitro and in vivo for their function in MPM tumours and reduction of immunosuppression in the TME. The M11-β-CAR-T cells were significantly more functional than conventional M11-CAR-T cells both in vitro and in vivo. In immunocompetent MPM mouse models, the M11-β-CAR was shown to significantly inhibit tumour growth, increase proliferation and function of endogenous tumour-infiltrating lymphocytes (TILs), and significantly increased the levels of neutrophils in the tumour. The increase in neutrophils was also determined to be required for the function of the M11-β-CAR-T cells and were found to be capable of spontaneous tumour killing in responding tumours.
This research is important as it will highlight the potential of M11-β-CAR-T cells in increasing CAR-T cell efficacy through limiting immunosuppression in the TME of MPM and enabling TME remodelling. The findings of this research will have an impact on treating other immunosuppressive solid tumours with armoured CAR-T cell therapy.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Thor Onco Immuno Group