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Unraveling cellular and molecular mechanisms of relapse in CD19/CD22 dual-targeting chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia

Leukemia (2026) Cite this article

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Abstract

CD19/CD22 dual-target chimeric antigen receptor (CAR19/22) T cell therapies mark a key advance over single-target options for refractory B-cell malignancies. However, over 20% of patients relapse and underlying mechanisms remain less understood. This study evaluated relapse in 91 B-cell acute lymphoblastic leukemia (B-ALL) patients treated with CAR19/22 T cells a clinical trial (ChiCTR-OPN-16008526). The complete remission rate was 91.9%, and 32.9% (26/79) of responders relapsed at a median of approximately 7 months. Among late relapses (>7 months), 92.3% was CAR T functional insufficiency showing lack of persistence or recovery of CD19⁺ B lymphocytes. Early relapses showed greater heterogeneity with 30.8% attributable to CAR T functional insufficiency and 30.8% to antigen insufficiency. Notably, two early relapses (15.4%) exhibited concurrent CD19/CD22 downregulation and harbored a preexisting PAX5 deletion or frameshift insertion. These PAX5-mutated subclones persisted and expanded at relapse, with one patient acquiring additional CD19 mutations. PAX5 knockout in leukemic cells reduced CD19/CD22 expression and proximal enhancer activities, causing in vitro resistance to CAR19/22 T cells. Collectively, CAR T functional insufficiency and antigen insufficiency are the most (61.5%) and second (15.4%) frequent drivers of relapse, respectively. Disruptive PAX5 mutations define a distinct molecular mechanism of early relapse, guiding rational targeted strategies.

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Fig. 1: Clinical outcomes and relapse-associated characteristics in patients receiving CAR19/22 T cell cocktail therapy.
The alternative text for this image may have been generated using AI.
Fig. 2: Antigen density and genomic alterations in CD19 and CD22 for early relapse patients with dual antigen downmodulation.
The alternative text for this image may have been generated using AI.
Fig. 3: Clonal evolution associated with PAX5 mutations under dual-target CAR19/22 T-cell therapy.
The alternative text for this image may have been generated using AI.
Fig. 4: PAX5 knockout results in downregulation of dual target antigens and reduced stimulation of CAR19/22 T cell activation.
The alternative text for this image may have been generated using AI.The alternative text for this image may have been generated using AI.
Fig. 5: Mechanistic model of B-ALL relapse post-dual-target CAR19/22 T-cell therapy.
The alternative text for this image may have been generated using AI.

Data availability

The raw sequencing data reported in this paper have been deposited into the Genome Sequence Archive [60] in National Genomics Data Center [61], China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA000038) that are accessible at https://ngdc.cncb.ac.cn/gsa-human. The release and use of these data have been approved by The Ministry of Science and Technology of the People’s Republic of China (permission number 2026BAT00383) and are available under controlled access. All other data supporting the findings of the study are included in the article and its Supplementary Tables 1–11. The public datasets used in this study are listed in Supplementary Table 6.

Code availability

WGS, RNA-seq, ChIP-seq, ATAC-seq data analysis codes used in this study are available from the corresponding authors on reasonable request.

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Acknowledgements

We thank the patients and their families for their participation in this study; the members of the following research cores at the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology: the Translational and Correlative Studies Laboratory, for their provision of standardized flow cytometry, qPCR and cytokine multiplexing analyses, as well as for their expert biobanking of patient specimens involved in CAR T cell trials, the Clinical Cell and Vaccine Production Facility for cell processing and biobanking, the Human Immunology Core for providing HD cells and analytical support, and the Flow Cytometry Core for flow cytometry equipment maintenance and access to electronic sorters; the members of the research and medical teams involved in the collection of patient samples, CAR T manufacturing, clinical administration and monitoring, and patient consent and recruitment. We also thank the staff at the High-Performance Computing clusters for facilitating computational data analysis in the China National Center for Bioinformation and the Beijing Institute of Genomics, Chinese Academy of Sciences. Fuhong He discloses support for publication of this work from the National Key R&D Program of China (2022YFF1202004). Qian-Fei Wang discloses support for the research of this work from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA0460403). Fuhong He discloses support for publication of this work from the National Natural Science Foundation of China (81970175). Wenyue Cao discloses support for the publication of this work from the National Natural Science Foundation of China (82200189).

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Author notes

  1. Deceased: Jianfeng Zhou

  2. These authors contributed equally: Jiaqi Tan, Fuhong He, Haiyang Hu, Wenyue Cao.

  3. These authors jointly supervised this work: Jianfeng Zhou, Qian-Fei Wang.

Authors and Affiliations

  1. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Jiaqi Tan

  2. Department of Haematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Jiaqi Tan, Wenyue Cao, Na Wang, Xingxing Zuo, Liang Huang & Jianfeng Zhou

  3. China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Fuhong He, Haiyang Hu & Qian-Fei Wang

  4. University of Chinese Academy of Sciences, Beijing, China

    Fuhong He, Haiyang Hu & Qian-Fei Wang

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Contributions

JT and WC processed samples, analyzed clinical data from B-ALL patients, and designed and performed functional experiments. FH and HH designed and conducted all bioinformatic analyses of genomic, transcriptomic, and epigenomic data from our cohort, public cohorts, and published datasets. FH, JT, WC, and HH analyzed and interpreted the data, and drafted the manuscript. NW, LH, and JZ conducted the clinical trial and managed patient care. XZ participated in data collection and assisting with functional experiments. JZ and QFW conceived and designed the research, interpreted the data, and supervised the manuscript preparation.

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Correspondence to Jianfeng Zhou or Qian-Fei Wang.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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This study was performed in accordance with the Declaration of Helsinki and written informed consent was obtained from each participant. Ethical approval was obtained from the Institutional Review Board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The clinical trial was registered in the Chinese Clinical Trial Registry with the number ChiCTR-OPN-16008526.

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Tan, J., He, F., Hu, H. et al. Unraveling cellular and molecular mechanisms of relapse in CD19/CD22 dual-targeting chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia. Leukemia (2026). https://doi.org/10.1038/s41375-026-02978-3

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