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Excessive activated T-cell proliferation after anti-CD19 CAR T-cell therapy

Gene Therapyvolume 25pages198204 (2018) | Download Citation

Abstract

Excessive activated T-cell proliferation was observed in vivo in one patient after an anti-CD19-chimeric antigen receptor (CAR) T-cell infusion. The patient, who had chemotherapy refractory and CD19+ diffuse large B-cell lymphoma (DLBCL), received an anti-CD19 CAR T-cell infusion following conditioning chemotherapy (fludarabine/cyclophosphamide). The lymphocyte count in the peripheral blood (PB) increased to 77 × 109/L on day 13 post infusion, and the proportion of CD8+ actived T cells was 93.06% of the lymphocytes. Then, the patient suffered from fever and hypoxaemia. Significant increases in serum cytokine, lactate dehydrogenase, aspartate aminotransferase (AST), alanine transaminase (ALT), and glutamic-oxalacetic transaminase (γ-GT) levels were observed. A high-throughput sequencing analysis for T-cell receptors (TCRs) and whole-genome sequencing were used to explore the mechanisms underlying this excessive T-cell proliferation. TCR diversity was demonstrated, but no special gene mutation was found. The patient was found to be infected with the John Cunningham polyomavirus (JCV). It cannot be ruled out the bystander activation pathway induced by JCV infections related the excessive activated T-cell proliferation. Although the clinical and laboratory data do not fully explain the reason for excessive T-cell proliferation after the anti-CD19 CAR T-cell infusion, the risk of this type of toxicity should be emphasized. This study was registered at www.clinicaltrials.gov as NCT01864889.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 81402566, 81472612), the grants the Science and Technology Planning Project of Beijing City (No. Z151100003915076 to W.-D.H.) and the National Key Research and Development Program of China (No. 2016YFC1303501 and 2016YFC1303504 to W.-D.H.).

Author contributions

W.-Y.Z., Y.L. and Z.-Q.W. designed and performed the in vitro experiment, analyzed the data, and wrote the manuscript; J.N., G.Y.-L. and D.H.-R. performed the in vitro experiments; Q.-M.Y. and W.C.-M. ensured compliance with regulatory requirements for the clinical trial; Y.W. supervised the manufacture of cells in infusion; W.-D.H. enroled patients in the study, analyzed the data, and wrote and reviewed the manuscript.

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Author notes

  1. These authors contributed equally: Wen-ying Zhang, Yang Liu.

  2. These authors jointly supervised this work: Zhi-qiang Wu, Wei-dong Han.

Affiliations

  1. Biotherapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China

    • Wen-ying Zhang
    • , Chun-meng Wang
    • , Qing-ming Yang
    •  & Wei-dong Han
  2. Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, 100853, China

    • Yang Liu
  3. Department of Immunology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, 100853, China

    • Yao Wang
    • , Ye-lei Guo
    • , Han-ren Dai
    •  & Wei-dong Han
  4. Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, 100853, China

    • Jing Nie
    • , Zhi-qiang Wu
    •  & Wei-dong Han

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Zhi-qiang Wu or Wei-dong Han.

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DOI

https://doi.org/10.1038/s41434-017-0001-8