분당차병원 / 박나희, 문용화*
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.
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 email@example.com.