CD97-directed CAR-T cells with enhanced persistence eradicate acute myeloid leukemia in diverse xenograft models

Chimeric antigen receptor (CAR)-T therapy on acute myeloid leukemia (AML) is hindered by the absence of a suitable tumor-specific antigen. Here, we propose CD97 as a potential target for CAR-T therapy against AML based on its broader and higher expression on AML cells compared to normal hematopoietic stem and progenitor cells (HSPCs). To resolve the fratricide problem caused by CD97 expression on T cells, we knock out CD97 in CAR-T cells using CRISPR-Cas9. Our CD97<sup>KO</sup> CAR-T cells eliminate both AML cell lines and primary AML cells effectively while showing tolerable toxicity to HSPCs. Furthermore, we mutate the CD3ζ domain of the CAR and find that the optimized CD97 CAR-T cells exhibit persistent anti-tumor activity both in vitro and in multiple xenograft models. Mechanistically, transcriptional profiles reveal that the optimized CAR-T cells delay differentiation and resist exhaustion. Collectively, our study supports CD97 as a promising target for CAR-T therapy against AML.

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Publication Details

Journal
Cell Reports Medicine
Published
2025-05-26
DOI
https://doi.org/10.1016/j.xcrm.2025.102148
Citations
3
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
3.14

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CD97-directed CAR-T cells with enhanced persistence eradicate acute myeloid leukemia in diverse xenograft models

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Cell Reports Medicine
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CD97-directed CAR-T cells with enhanced persistence eradicate acute myeloid leukemia in diverse xenograft models

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article en
3 citations

Abstract

Chimeric antigen receptor (CAR)-T therapy on acute myeloid leukemia (AML) is hindered by the absence of a suitable tumor-specific antigen. Here, we propose CD97 as a potential target for CAR-T therapy against AML based on its broader and higher expression on AML cells compared to normal hematopoietic stem and progenitor cells (HSPCs). To resolve the fratricide problem caused by CD97 expression on T cells, we knock out CD97 in CAR-T cells using CRISPR-Cas9. Our CD97<sup>KO</sup> CAR-T cells eliminate both AML cell lines and primary AML cells effectively while showing tolerable toxicity to HSPCs. Furthermore, we mutate the CD3ζ domain of the CAR and find that the optimized CD97 CAR-T cells exhibit persistent anti-tumor activity both in vitro and in multiple xenograft models. Mechanistically, transcriptional profiles reveal that the optimized CAR-T cells delay differentiation and resist exhaustion. Collectively, our study supports CD97 as a promising target for CAR-T therapy against AML.

Cell Reports MedicineVol. 6(6)
First People's Hospital of Yuhang District (CN), Second Affiliated Hospital of Zhejiang University (CN), First Affiliated Hospital Zhejiang University (CN), Zhejiang University (CN)
National Natural Science Foundation of China, Zhejiang University, Fundamental Research Funds for the Central Universities, Natural Science Foundation of Zhejiang Province
Zero hunger
Openalex Percentile: Top 8%
CAR-T cell therapy research
3.14
DOIOpen Access PDFOpenAlex
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