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Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models

 Kyoung Ho Pyo  ;  Jae Hwan Kim  ;  Ji-Min Lee  ;  Sung Eun Kim  ;  Jae Seok Cho  ;  Sun Min Lim  ;  Byoung Chul Cho 
 LUNG CANCER, Vol.127(1) : 112-121, 2019 
Journal Title
Issue Date
EML4-ALK ; Hu-PBL-NSG ; Humanized mouse ; Immunotherapy
BACKGROUND: With the advance of immunotherapy, treatment of non-small-cell lung cancer (NSCLC) has revolutionized by having anti-PD-1 therapy in front-line setting. In this era of cancer immunotherapy, humanized mouse models which recapitulate human immune system, are needed for predicting immunotherapy response in patients. We established a Hu-PBL-NSG mouse model which can be used as a preclinical testing platform for assessing efficacy of different immunotherapeutic agents.

MATERIALS AND METHODS: Hu-PBL-NSG mouse model was established by engrafting human peripheral blood mononuclear cells (PBMCs) into NOD/scid/IL-2Rγ-/- (NSG) mice. Cytokine array was performed to assess serological similarity between patient and the Hu-PBL-NSG mouse, and microscopic immune cell infiltration was observed in various organs mouse model. Human anti-PD-1 therapy was treated for assessing drug efficacy in patient-derived tumor.

RESULTS: hCD3+hCD45+ T-cells and antigen presenting cells (dendritic cells, macrophages, and MDSC) increased in the serum of Hu-PBL-NSG mouse 24 h after the transfusion of human PBMCs, and CD3 + T cells were observed in lung, liver, kidney, spleen sections. Cytokine arrays of human and Hu-PBL-NSG mouse revealed high similarity of Th1, Th2, Th17-related cytokines. A tumor xenograft was engrafted from an EML4-ALK patient, and Hu-PBL-NSG mouse was sacrificed for histological analyses. hCD3+ T cells were infiltrated within the tumor, and CD11c + cells, which represent antigen-presenting capability, were seen in spleen, lung, liver and kidney. When anti-PD-1 Ab was treated intraperitoneally, xenograft tumor showed significant reduction in volume after day 6, and increased expression of immune response-related genes on microarray analysis in the tumor. Mostly IFN-gamma and its related gene sets were significantly changed (FDR < 0.25, GSEA).

CONCLUSION: Hu-PBL-NSG mouse model which highly resembles human immune system was successfully established. This model could be a strong preclinical model for testing efficacy of immunotherapeutic agents, and also for pursuing novel immunotherapy treatment strategies in advanced NSCLC.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Pyo, Kyoung Ho(표경호) ORCID logo https://orcid.org/0000-0001-5428-0288
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