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J. Immunother. Cancer, Online issue publication November 25, 2020 | doi: 10.1136/jitc-2020-001513 Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

Nahee Park¹, Kamal Pandey^1,2, Sei Kyung Chang³, Ah-Young Kwon⁴, Young Bin Cho¹, Jin Hur^1,2, Nar Bahadur Katwal^1,2, Seung Ki Kim⁵, Seung Ah Lee⁵, Gun Woo Son¹, Jong Min Jo¹, Hee Jung Ahn⁴ and Yong Wha Moon^1,*

¹Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea
²Department of Biomedical Science, CHA Bundang Medical Center, Seongnam, South Korea
³Department of Radiation Oncology, CHA Bundang Medical Center, Seongnam, South Korea
⁴Department of Pathology, CHA Bundang Medical Center, Seongnam, South Korea
⁵Department of Surgery, CHA Bundang Medical Center, Seongnam, South Korea

^*Correspondence to Dr Yong Wha Moon

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.

논문정보

형식Research article
게재일2020년 11월 (BRIC 등록일 2021-01-15)
연구진국내 연구진
분야 의약학 > 종양의학

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