PT  - JOURNAL ARTICLE
AU  - Park, Nahee
AU  - Pandey, Kamal
AU  - Chang, Sei Kyung
AU  - Kwon, Ah-Young
AU  - Cho, Young Bin
AU  - Hur, Jin
AU  - Katwal, Nar Bahadur
AU  - Kim, Seung Ki
AU  - Lee, Seung Ah
AU  - Son, Gun Woo
AU  - Jo, Jong Min
AU  - Ahn, Hee Jung
AU  - Moon, Yong Wha
TI  - Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model
AID  - 10.1136/jitc-2020-001513
DP  - 2020 Nov 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e001513
VI  - 8
IP  - 2
4099  - http://jitc.bmj.com/content/8/2/e001513.short
4100  - http://jitc.bmj.com/content/8/2/e001513.full
SO  - J Immunother Cancer2020 Nov 01; 8
AB  - 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.