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  • [J Immunother Cancer.] Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

    분당차병원 / 박나희, 문용화*

  • 출처
    J Immunother Cancer.
  • 등재일
    2020 Nov
  • 저널이슈번호
    8(2):e001513. doi: 10.1136/jitc-2020-001513.
  • 내용

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    Abstract
    Background: Well-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.

    Methods: Humanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.

    Results: Busulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.

    Conclusions: Our CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.

     

     

    Affiliations

    Nahee Park  1 , Kamal Pandey  1   2 , Sei Kyung Chang  3 , Ah-Young Kwon  4 , Young Bin Cho  1 , Jin Hur  1   2 , Nar Bahadur Katwal  1   2 , Seung Ki Kim  5 , Seung Ah Lee  5 , Gun Woo Son  1 , Jong Min Jo  1 , Hee Jung Ahn  4 , Yong Wha Moon  6
    1 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea.
    2 Department of Biomedical Science, CHA Bundang Medical Center, Seongnam, South Korea.
    3 Department of Radiation Oncology, CHA Bundang Medical Center, Seongnam, South Korea.
    4 Department of Pathology, CHA Bundang Medical Center, Seongnam, South Korea.
    5 Department of Surgery, CHA Bundang Medical Center, Seongnam, South Korea.
    6 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea ymoon@cha.ac.kr.

  • 키워드
    immunotherapy.
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