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Immunotherapy

A novel chimeric antigen receptor redirecting T-cell specificity towards CD26+ cancer cells

Leukemia volume 35, pages 119–129 (2021)Cite this article

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Abstract

Chimeric antigen receptor (CAR) T-cell immunotherapy is rapidly emerging as a promising novel treatment for malignancies. To broaden the success of CAR T-cell treatment for chronic myeloid leukaemia (CML), we attempted to construct a CD26 CAR T-cell product to target tyrosine kinase inhibitor-insensitive leukaemia stem cells (LSCs), which have been a challenge to cure for several decades and can be discriminated from healthy stem cells by the robust biomarker CD26. Of additional interest is that CD26 has also been reported to be a multi-purpose therapeutic target for other malignancies. Here, we constructed CD26 CAR T cells utilizing lentiviral transduction methods and verified them by flow cytometry analysis and RNA-seq. We found that the initial expansion of CD26 CAR-transduced T cells was delayed due to transient fratricide, but subsequent expansion was accelerated. CD26 CAR T cells exhibited cytotoxicity against the CD26+ T-cell lymphoma cell line Karpas 299, CD26-overexpressing K562 cells and primary CML LSCs, activated multiple effector functions in co-culture assays, and limited tumour progression in a mouse model; but there was some off-tumour cytotoxicity towards activated lymphocytes. In conclusion, these results establish the feasibility of using CD26 as an antigen for CAR T cells targeting CD26+ tumour cells.

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Fig. 1: CD26 CAR T-cell construction and characterization.
Fig. 2: The gene expression of CD26 CAR T cells.
Fig. 3: Specific cytotoxicity of CD26 CAR T cells against Karpas 299 cells.
Fig. 4: Specific cytotoxicity of CD26 CAR T cells against CD26+ K562 cells in vitro.
Fig. 5: Cytotoxicity against primary CD34+CD26+ cells from CML patients.
Fig. 6: The potential side effects of CD26 CAR T cells on healthy haematopoietic cells.

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Acknowledgements

The work was supported by grants from the National Natural Science Foundation of China (NSFC) (Nos: 81873440, 81700142 and 81670145). We appreciate all of the doctors and patients who have contributed to this work.

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  1. These authors contributed equally: Shu Zhou, Weiming Li

Authors and Affiliations

  1. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Shu Zhou, Weiming Li, Xiaoying Zhu, Zhaodong Zhong, Fanjun Cheng, Ping Zou & Yong You

  2. Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Yi Xiao & Xiaojian Zhu

  3. Department of Hematology, Wuhan No.1 Hospital, Wuhan, 430022, China

    Qing Li

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Contributions

XJZ and YY designed the research; WML, YY and YX provided the samples and technical support; SZ and XYZ performed experiments; QL, XYZ and SZ analyzed results and made the figures; XJZ and SZ wrote the paper; FJC, ZDZ and PZ interpreted data and reviewed the paper.

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Correspondence to Yong You or Xiaojian Zhu.

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Zhou, S., Li, W., Xiao, Y. et al. A novel chimeric antigen receptor redirecting T-cell specificity towards CD26+ cancer cells. Leukemia 35, 119–129 (2021). https://doi.org/10.1038/s41375-020-0824-y

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