MicroRNA-142 improves IL1RAP CAR-T cell activity in acute myeloid leukemia
Rattachement africain : jp, us, cn. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
BACKGROUND: Interleukin-1 receptor accessory protein (IL1RAP) is selectively expressed on both bulk blasts and leukemic stem cells (LSCs) in acute myeloid leukemia (AML), while its expression is virtually absent on normal hematopoietic stem cells (HSCs), making it an appealing target for chimeric antigen receptor (CAR) T cell therapy. METHODS: We developed a novel IL1RAP-targeting CAR-T cells using a single-chain Fab (24scFab) fused to CD28 and CD3ζ costimulatory domains. CAR-T cells with a mutated IL1RAP-binding paratope were also generated as a control by introducing two point-mutations in the complementarity determining region (CDR) loops of the 24scFab domain. We tested the CAR-T cells in cell line-derived (CD) and patient-derived (PD) xenografts (X). To address persistence and activity of IL1RAP CAR-T cells, we then tested two approaches. First, we mutated two of the three immunoreceptor tyrosine-based activation motifs (ITAMs) within the CD3ζ domain (i.e., IL1RAP-1XX CAR-T). Second, we co-administered a synthetic miR-142 mimic (M-miR-142), previously shown to enhance T cell antileukemic activity, with IL1RAP CAR-T cells to AML xenografted mice. RESULTS: IL1RAP CAR-T cells demonstrated a potent antileukemic activity in both AML CDX and PDX models. Target specificity was confirmed by the complete loss of function of IL1RAP-mutated CAR-T cells. IL1RAP-1XX CAR-T cells improved T cell persistence in vitro but failed to demonstrate therapeutic benefit compared with IL1RAP CAR-T cells in vivo. We previously reported that leukemic cell growth suppresses miR-142 biogenesis, thereby hindering the metabolic switch and impairing host T cell antileukemic activity; this was rescued by administration of M-miR-142. Thus, we hypothesized a similar impact of leukemic cells on CAR-T and that M-miR-142 treatment could rescue it and enhance the IL1RAP CAR-T cell antileukemic activity. We showed that both CDXs and PDXs receiving M-miR-142 and IL1RAP CAR-T lived significantly longer than those receiving scrambled oligonucleotide and IL1RAP CAR-T or mutated CAR-T controls (median survival of PDX: 78 vs 51 vs 24 days). CONCLUSIONS: We have identified a potentially novel strategy to enhance CAR-T cell persistence and efficacy in AML by counteracting a leukemia-induced, microRNA-deficiency mediated mechanism of immune suppression.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- MicroRNA-142 improves IL1RAP CAR-T cell activity in acute myeloid leukemia
- Date Crossref
- 12/11/2025
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Tokai University Department of Hematology and Oncology pays non établi dans la noticeUniversité ou école supérieure
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City of Hope Department of Hematological Malignancies Translational Science pays non établi dans la noticeÉtablissement de santé
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Tokai University Hospital pays non établi dans la noticeÉtablissement de santé
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Beckman Research Institute Department of Cancer Biology and Molecular Medicine pays non établi dans la noticeStructure de recherche
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Westlake University Affiliated Hangzhou First People's Hospital pays non établi dans la noticeÉtablissement de santé
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First Affiliated Hospital Zhejiang University pays non établi dans la noticeÉtablissement de santé
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City Of Hope National Medical Center pays non établi dans la noticeÉtablissement de santé
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College of Medicine Department of Hematology pays non établi dans la noticeUniversité ou école supérieure
Department of Hematology and Oncology — Tokai University, Department of Hematological Malignancies Translational Science — City of Hope et Tokai University Hospital, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.