Cre-dependent gene expression enables thymic development of autoreactive tumor-associated antigen targeting CAR-T cells
Chimeric antigen receptor (CAR)-T cells have revolutionized cancer therapy by enabling highly specific adoptive cellular treatments. However, limited in vivo persistence and tumor relapse remain major challenges. To address this, we developed a platform for continuous in vivo generation of CAR-T cel...
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| Autores principales: | , , , , , , , , , , , , , , , , , |
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| Formato: | Article (Journal) |
| Lenguaje: | inglés |
| Publicado: |
1 April 2026
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| In: |
Molecular therapy
Year: 2026, Volumen: 34, Número: 4, Pages: 1945-1953 |
| ISSN: | 1525-0024 |
| DOI: | 10.1016/j.ymthe.2025.12.047 |
| Acceso en línea: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ymthe.2025.12.047 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1525001625010706 
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| Notas de Autor: | Manpreet Bariana, Michael McGuire, Andrea Tuckett, Elena Cassella, Sidharth Anand, Shaina A. Anuncio, Sara Mina, Sharoni Avtalion, Megan A. Lloren, Nicolai Bogert, Mathias Konstandin, Justin Boucher, Nolan Beatty, Shannon McSain, Wei Hu, Hai-Hui Xue, Marco L. Davila, Johannes L. Zakrzewski |
| Sumario: | Chimeric antigen receptor (CAR)-T cells have revolutionized cancer therapy by enabling highly specific adoptive cellular treatments. However, limited in vivo persistence and tumor relapse remain major challenges. To address this, we developed a platform for continuous in vivo generation of CAR-T cells by genetically engineering hematopoietic stem and progenitor cells to express a tumor-specific CAR followed by administration directly into the thymus. We demonstrated in single-cell RNA sequencing and serial transplantation studies that the thymic microenvironment supports short-term hematopoietic stem cells and initiates a transcriptional program that drives T cell lineage differentiation. A key challenge of thymic CAR-T cell development is thymic negative selection, which eliminates developing thymocytes expressing autoreactive antigen receptors such as CD19 CARs. We show that reducing CAR co-stimulation and modifying the endogenous T cell receptor repertoire can enhance the survival of these cells during thymic development. Additionally, inducible CAR gene expression enables sustained thymic production of CD19 CAR-T cells, which can target both normal B cells and CD19+ tumor cells. Our findings highlight mechanisms governing the fate of CAR-T cell precursors in the thymus and support inducible expression systems as a strategy to bypass central tolerance, offering a path toward durable, self-renewing CAR-T cell therapies. |
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| Notas: | Online verfügbar: 24. Dezember 2025, Artikelversion: 1. April 2026 Gesehen am 04.08.2026 Online veröffentlicht: 8. April 2026 |
| Descripción Física: | Online Resource |
| ISSN: | 1525-0024 |
| DOI: | 10.1016/j.ymthe.2025.12.047 |