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Development of TCR-T cell therapy targeting mismatched HLA-DPB1 for relapsed leukemia after allogeneic transplantation

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Abstract

Relapsed leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a significant challenge, with the re-emergence of the primary disease being the most frequent cause of death. Human leukocyte antigen (HLA)-DPB1 mismatch occurs in approximately 70% of unrelated allo-HSCT cases, and targeting mismatched HLA-DPB1 is considered reasonable for treating relapsed leukemia following allo-HSCT if performed under proper conditions. In this study, we established several clones restricted to HLA-DPB1*02:01, -DPB1*04:02, and -DPB1*09:01 from three patients who underwent HLA-DPB1 mismatched allo-HSCT using donor-derived alloreactive T cells primed to mismatched HLA-DPB1 in the recipient’s body after transplantation. A detailed analysis of the DPB1*09:01-restricted clone 2A9 showed reactivity against various leukemia cell lines and primary myeloid leukemia blasts, even with low HLA-DP expression. T cell receptor (TCR)-T cells derived from clone 2A9 retained the ability to trigger HLA-DPB1*09:01-restricted recognition and lysis of various leukemia cell lines in vitro. Our study demonstrated that the induction of mismatched HLA-DPB1 specific T cell clones from physiologically primed post-allo-HSCT alloreactive CD4+ T cells and the redirection of T cells with cloned TCR cDNA by gene transfer are feasible as techniques for future adoptive immunotherapy.

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Data will be available on reasonable request to the corresponding author.

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Acknowledgements

We would like to thank all members of the Department of Immunology, Nagoya University Graduate School of Medicine for their valuable technical support and insightful discussions during the course of the study. We would also like to express our gratitude to the staff of the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for their valuable technical support. This study was supported in part by Grants-in-Aid for Scientific Research (grant no. 21K08369 to YA) from the Ministry of Education, Culture, Sports, Science, by AMED (grant no. JP21ek0510027 to YA) and Aichi Cancer Research Foundation (to YA).

Author information

Authors and Affiliations

  1. Department of Immunology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan

    Carolyne Barakat, Naoya Katsuyama, Yoshie Sato, Hiroyoshi Nishikawa & Yoshiki Akatsuka

  2. Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan

    Yuichiro Inagaki & Masashi Sawa

  3. Division of Hematology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan

    Shohei Mizuno

  4. Center for Advanced Medicine and Clinical Research, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan

    Nobuhiro Nishio

  5. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Nobuhiro Nishio & Yoshiyuki Takahashi

  6. Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan

    Miki Kobayashi

  7. Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, Konan, Japan

    Kazutaka Ozeki

  8. Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Hiroatsu Iida

  9. Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan

    Akihiro Tomita

  10. Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan

    Ayako Demachi-Okamura

  11. Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Japan

    Hiroyoshi Nishikawa

Authors
  1. Carolyne Barakat
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  2. Yuichiro Inagaki
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  3. Shohei Mizuno
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  4. Nobuhiro Nishio
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  7. Miki Kobayashi
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  8. Kazutaka Ozeki
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  9. Hiroatsu Iida
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  10. Akihiro Tomita
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  11. Masashi Sawa
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  12. Ayako Demachi-Okamura
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  13. Yoshiyuki Takahashi
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  14. Hiroyoshi Nishikawa
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  15. Yoshiki Akatsuka
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Contributions

YA designed the experiments. CB, NK, YS, and YA performed the experiments. YI, SM, MK, KO, HI, AT, and MS collected and provided the clinical samples. NN, AD-O, YT, and HN provided technical support. CB and YA wrote the manuscript. YA secured the funds. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Yoshiki Akatsuka.

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Conflict of interest

YA received honoraria and research funding from Bristol-Myers Squibb. All other authors declare no competing financial interests.

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Barakat, C., Inagaki, Y., Mizuno, S. et al. Development of TCR-T cell therapy targeting mismatched HLA-DPB1 for relapsed leukemia after allogeneic transplantation. Int J Hematol 118, 252–266 (2023). https://doi.org/10.1007/s12185-023-03621-y

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  • DOI: https://doi.org/10.1007/s12185-023-03621-y

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