Abstract
The prognosis of relapsed or refractory acute myeloid leukemia (r/r AML) patients remains poor due to lack of novel therapies. We previous demonstrated that chimeric antigen receptor (CAR) T cells targeting CD64 have the potential to treat AML with minimal toxicity to hematopoietic stem/progenitor cells. However, the efficacy was limited in AML mouse models. Interleukin-15 (IL-15), a cytokine that promotes T cell survival and proliferation, has been shown to enhance CAR T cell activity. Here, we engineer CD64 CAR T cells with overexpression of IL-15 and evaluate the function. IL-15-armed CAR T cells exhibit enhanced cytolytic activity against AML cells, improve expansion and persistence in vitro, and favor a memory phenotype while reducing exhaustion and apoptosis. In mouse model, IL-15-armed CAR T cells show robust expansion, prolong mouse survival, and no obvious toxicity. These findings suggest that IL-15-armed CD64 CAR T cells may be a promising strategy for r/r AML.
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Data availability
The corresponding author will address reasonable requests for datasets associated with this study, with a processing time of approximately three months. All essential data underpinning our conclusions are available within this article. RNA-seq data is available in the Genome Sequence Archive (GSA) database (https://ngdc.cncb.ac.cn/gsa-human/) under accession number HRA015107. Source data are provided in Supplementary Data 1.
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Acknowledgements
We thank all members of our team for the critical discussion and suggestions. This work was supported by the following funders: CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-017), the National Key R&D Program of China (2021YFA1100703), the National Natural Science Foundation of China (32170891) and start-up funding from Hangzhou Normal University. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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L.S. and X.F. designed the experiments. L.S. performed the majority of the experiments, generated experimental data. L.S. and X.F. wrote the manuscript. C.L. assisted with in vivo experiments. T.L. and C.W. assisted with some experiments during the revision process. H.C., A.P. and X.F. provided support and supervised the study. All authors are in agreement on the final version of the manuscript.
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Shan, L., Li, C., Li, T. et al. IL-15 overexpression promotes memory program and anti-tumor activity of CD64 CAR T cells in a preclinical AML model. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09528-8
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DOI: https://doi.org/10.1038/s42003-026-09528-8
