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Targeting fibroblast activation protein in solid tumors via LNP-mediated CAR-mRNA delivery promotes durable
Sikun Meng1, Tomoaki Hara1, Tetsuya Sato2
1Department of Medical Data Science, Center of Medical Innovation and Translational Research, Graduate School of Medicine, The University of Osaka, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
Abstract:
The therapeutic potential of chimeric antigen receptor (CAR) T-cell therapy in treating solid tumors is highly recognized, yet the complex and immunosuppressive nature of the tumor microenvironment, poor accessibility, and the instability of target antigens pose substantial challenges. Here, we present an mRNA-LNP-based therapeutic strategy that delivers mRNA encoding a fibroblast activation protein (FAP)-specific CAR to reprogram host immune cells in vivo and target cancer-associated fibroblasts within the tumor stroma. In multiple solid tumor mouse models, this approach, combined with chemotherapeutic agents and immune checkpoint inhibitors, achieved significant tumor regression and induced durable, antigen-specific immune memory. Incorporation of m6A-modified CAR mRNA accelerated and amplified antitumor responses, while blockade of the macrophage migration inhibitory factor (MIF)-CD74 axis further improved tumor control by alleviating immune suppression. In patient-derived xenograft models, HOX family transcription factors were implicated in treatment resistance, highlighting a potential biomarker and therapeutic target. The evidence from this study demonstrates that targeting the tumor microenvironment with a controllable mRNA-modulated strategy achieves substantial antitumor efficacy and holds significant potential to enhance the applicability and acceptance of CAR-T cell therapy across a variety of cancers.
Insights
This study introduces an mRNA-LNP therapy targeting cancer-associated fibroblasts to enhance chimeric antigen receptor (CAR) T-cell therapy for solid tumors. The novel approach improved tumor regression and immune memory, offering new possibilities for cancer treatment.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise for solid tumors but faces challenges from the tumor microenvironment.
- Targeting cancer-associated fibroblasts (CAFs) is a strategy to overcome these hurdles.
- Fibroblast activation protein (FAP) is a key target within the tumor stroma.
Purpose of the Study:
- To develop and evaluate an in vivo mRNA-LNP-based CAR T-cell reprogramming strategy targeting FAP.
- To assess the combination therapy's efficacy with chemotherapy and immune checkpoint inhibitors.
- To explore mechanisms of resistance and identify potential biomarkers.
Main Methods:
- An mRNA-LNP delivery system encoding a FAP-specific CAR was developed.
- In vivo reprogramming of host immune cells was performed in solid tumor mouse models.
- Combination treatments included chemotherapeutic agents and immune checkpoint inhibitors.
- Macrophage migration inhibitory factor (MIF)-CD74 axis blockade and m6A modification of mRNA were investigated.
- Patient-derived xenograft models were used to study treatment resistance.
Main Results:
- The mRNA-LNP-FAP-CAR strategy demonstrated significant tumor regression in multiple solid tumor models.
- Durable, antigen-specific immune memory was induced post-treatment.
- m6A modification of CAR mRNA enhanced and accelerated antitumor responses.
- MIF-CD74 axis blockade improved tumor control by reducing immune suppression.
- HOX family transcription factors were identified as potential resistance factors in xenograft models.
Conclusions:
- In vivo mRNA-based CAR T-cell therapy targeting the tumor microenvironment offers a potent strategy against solid tumors.
- Combination with chemotherapy, immune checkpoint inhibitors, and MIF-CD74 blockade enhances efficacy.
- This approach holds potential to broaden the application and acceptance of CAR T-cell therapy in oncology.
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