Myocardial fibrosis is an irreversible pathological consequence that occurs as various heart diseases progress to their end stages. Currently, no effective therapeutic strategies have been established in clinical practice for its management. The development of T-cell therapy offers promising and innovative opportunities for the treatment of myocardial fibrosis. In this study, we employed CD3-targeted lipid nanoparticles (LNPs) to efficiently deliver the designed chimeric antigen receptor (CAR) structure and the molecular switch HuEGFRt mRNA into T cells, thereby successfully constructing CAR-T cells targeting fibroblast activation protein (FAP). The experimental results demonstrated that FAP-CAR-T cells could specifically eliminate target cells with high FAP expression while exhibiting minimal cytotoxicity on normal cells. Furthermore, the in vivo-generated FAP-CAR-T cells significantly alleviated myocardial fibrosis and effectively improved cardiac function. Regarding safety evaluation, the introduced molecular switch HuEGFRt could selectively induce apoptosis of CAR-T cells via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in the presence of cetuximab. Blood routine and biochemistry test results confirmed that the in vivo-generated FAP-CAR-T cells did not elicit any adverse reactions in the mouse model. Therefore, the in vivo generation of FAP-CAR-T cells via LNPs targeting CD3 represents an effective and safe therapeutic strategy for treating myocardial fibrosis. This innovative method not only exhibits substantial therapeutic potential but also expands the clinical application prospects for patients with myocardial fibrosis.

2025-09-01·Molecular Therapy-Methods & Clinical Development

FAP-CAR-T cells reduce dystrophic muscle fibrosis, improving adeno-associated virus gene transfer efficacy

Article

作者: Bôle-Richard, Elodie ; Corre, Guillaume ; Galy, Anne ; Ferrand, Maxime ; Rocca, Céline J ; Buffa, Valentina ; Richard, Isabelle ; Garnache-Ottou, Francine ; Albini, Sonia ; Frin, Sophie

Tissue fibrosis is a pathological feature of many diseases including muscular dystrophies such as Duchenne muscular dystrophy (DMD). Fibrosis may limit the effectiveness of gene therapy in muscle impacting on viral dosing but direct evidence is lacking. Strategies to reduce skeletal muscle fibrosis are limited. The fibrosis Fap gene is over-expressed in the skeletal muscles of a severe mouse model of DMD, suggesting that cells expressing membrane fibroblast activation protein (FAP) could be targeted by chimeric antigen receptor (CAR)-T cells. Two consecutive administrations of FAP-specific CAR-T cells in the severe DMD model reduced collagen deposits and fibrotic biomarkers and also reduced the number of FAP-positive cells in muscle. Single cell transcriptomics revealed that FAP-CAR-T cells triggered cellular interactions with otherwise inactive muscle resident macrophages and depleted specific subsets of FAP-highly-expressing fibro-adipogenic progenitor cells, pointing to their importance in the fibrosis process. Reducing fibrosis with FAP-CAR-T cells enhanced adeno-associated virus (AAV) microdystrophin gene transfer in the model by increasing vector copies, demonstrating that fibrosis is a restriction factor for AAV gene delivery in skeletal muscle. These results provide novel insights into therapeutic strategies for DMD or other fibrotic diseases.

2022-12-15·Clinical cancer research : an official journal of the American Association for Cancer Research

Monitoring Therapeutic Response to Anti-FAP CAR T Cells Using [18F]AlF-FAPI-74

Article

作者: Xiao, Zebin ; June, Carl H. ; Noguera-Ortega, Estela ; Farwell, Michael D. ; Scholler, John ; Edwards, Kimberly J. ; Sellmyer, Mark A. ; Liousia, Maria ; Lee, Iris K. ; Puré, Ellen ; Xu, Kexiang ; Albelda, Steven M. ; Todd, Leslie ; Song, Decheng ; Lohith, Katheryn

Abstract:

Purpose::

Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. Our understanding of the limited therapeutic efficacy in solid tumors could be improved with quantitative tools that allow characterization of CAR T–targeted antigens in tumors and accurate monitoring of response.

Experimental Design::

We used a radiolabeled FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe to complement ongoing efforts to develop and optimize FAP CAR T cells. The selectivity of the radiotracer for FAP was characterized in vitro, and its ability to monitor changes in FAP expression was evaluated using rodent models of lung cancer.

Results::

[18F]AlF-FAPI-74 showed selective retention in FAP+ cells in vitro, with effective blocking of the uptake in presence of unlabeled FAPI. In vivo, [18F]AlF-FAPI-74 was able to detect FAP expression on tumor cells as well as FAP+ stromal cells in the tumor microenvironment with a high target-to-background ratio. We further demonstrated the utility of the tracer to monitor changes in FAP expression following FAP CAR T-cell therapy, and the PET imaging findings showed a robust correlation with ex vivo analyses.

Conclusions::

This noninvasive imaging approach to interrogate the tumor microenvironment represents an innovative pairing of a diagnostic PET probe with solid tumor CAR T-cell therapy and has the potential to serve as a predictive and pharmacodynamic response biomarker for FAP as well as other stroma-targeted therapies. A PET imaging approach targeting FAP expressed on activated fibroblasts of the tumor stroma has the potential to predict and monitor therapeutic response to FAP-targeted CAR T-cell therapy.See related commentary by Weber et al., p. 5241

100 项与 FAP靶向的CAR-T(Capstan Therapeutics) 相关的药物交易

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