RT Journal Article
SR Electronic
T1 Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e001513
DO 10.1136/jitc-2020-001513
VO 8
IS 2
A1 Nahee Park
A1 Kamal Pandey
A1 Sei Kyung Chang
A1 Ah-Young Kwon
A1 Young Bin Cho
A1 Jin Hur
A1 Nar Bahadur Katwal
A1 Seung Ki Kim
A1 Seung Ah Lee
A1 Gun Woo Son
A1 Jong Min Jo
A1 Hee Jung Ahn
A1 Yong Wha Moon
YR 2020
UL http://jitc.bmj.com/content/8/2/e001513.abstract
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.