Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model.
J Immunother Cancer
; 8(2)2020 11.
Article
em En
| MEDLINE
| ID: mdl-33239416
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.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Antígenos CD34
/
Imunoterapia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Immunother Cancer
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Coréia do Sul