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

Abstract

BackgroundWith 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 methodsHu-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. ResultshCD3+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). ConclusionHu-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.