Augmented FAP CAR T cell Therapy for the Treatment of Malignant Pleural Mesothelioma
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Embargo End Date
2025-10-03
ICR Authors
Authors
Bughda, R
Document Type
Thesis or Dissertation
Date
2025-04-03
Date Accepted
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive and incurable cancer mainly caused by asbestos exposure. Chimeric antigen receptor (CAR) T-cell therapies are targeted immunotherapies currently being trialled for solid cancers, including MPM. However, despite their success in haematological malignancies, their efficacy in solid malignancies has been limited so far partly due to the hostile solid tumour microenvironment (TME). Two elements in MPM’s TME that pose significant barriers to CAR T-cells are cancer associated fibroblasts (CAFs) in the tumour stroma, and TGF-β, a highly
This project aims to augment FAP CAR T-cells by utilizing TGF-β via two methodologies. First, via re-engineering of FAP CAR T-cells to secrete TGF-β inhibiting peptides that reduce TME immunosuppression. Second, via FAP CAR T-cell differentiation, with the use of exogenous TGF-β, into a “tissue resident”. Phenotype.
Proof principal studies showed that peptides P17 and P144 inhibit TGF-β activity in vitro and in vivo. Attempts to incorporate the peptides into the lentiviral backbone of the human FAP CAR have been unsuccessful; however the peptides were incorporated into the retroviral murine FAP CAR, whose efficacy and toxicity was assessed in vitro and in vivo. FAP CAR T-cells with tissue resident phenotype were also successfully generated and were tested in vitro 2D and 3D MPM cultures. Ultimately, this project explored how the inhibition of TGF-β in the MPM TME contributes to TME differentiation into a more immunogenic phenotype.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Thor Onco Immuno Group