ArticleJournal of hematology & oncology2025
MicroRNA-142 improves IL1RAP CAR-T cell activity in acute myeloid leukemia.
Article in Journal of hematology & oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- IL1RAP Antibody-Drug Conjugates Potently Target Primary and Metastatic Diseases in Multiple Oncofusion-Driven Cancers.Cancer discovery · 2026Article
- The search for safe and effective CAR-T targets in AML.Blood cancer journal · 2026Review
- Genomic context of mutations in MIR142 in blood cancers: summary and integrative analysis.Cellular & molecular biology letters · 2026Review
- miR-2110 orchestrates ERK-ELK1 transcriptional repression to induce cell-cycle arrest and enhance cytarabine sensitivity in acute myeloid leukemia.Frontiers in oncology · 2026Article
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18 authors.
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Abstract
backgroundInterleukin-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.
methodsWe 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.
resultsIL1RAP 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).
conclusionsWe 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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