Abstract
INTRODUCTION: We previously developed a humanized mouse model of chordomas, which allowed us to investigate the interaction between human chordomas and human immune cells. This platform is particularly useful for studying immunotherapy against rare cancers such as chordomas, where murine equivalents are currently unavailable. We aim to utilize this model to study synergism between PD-1 blockade and LXR-623, a synthetic agonist of liverX receptors, a class of anti-neoplastic agents disrupting cancer cholesterol-metabolism. Our preliminary data suggest that LXR-623 downregulates PD-L1 on chordoma cell lines and reduces immunosuppressive myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. METHODS: To achieve immune system reconstitution/humanization, 20 NSG-SGM3 mice were engrafted with human fetal thymus and CD34+ stem cells, whose HLA-types were partially-matched with those of the U-CH1 chordoma cell lines. They were divided into the following groups (n=5 for each group): control group (isotype antibodies (Abs) + vehicle), LXR-623 monotherapy group (isotype Abs + LXR-623 100mg/kg, i.p., daily for 4 weeks), anti-PD-1 Abs monotherapy group (anti-human-PD-1-Abs (Clone: J116), 10 mg/kg, i.p., 3 times/week for 4 weeks), and combination group (anti-human-PD-1 Abs + LXR-623). Anti-tumor activities will be monitored via tumor size measurement, flow cytometric analyses of peripheral blood and spleen as well as chordomas, using various Abs including anti-mouse-CD45, anti-human-CD3, anti-human-CD4, anti-human-CD8, anti-human-CD11b, anti-human-CD14, anti-human-CD15, anti-human-CD19, anti-human-CD25, anti-human-CD45, anti-human-CD45RA, anti-human-CD45RO, anti-human-PD-1, and anti-human-FoxP3, multiplex cytokine analyses including IFN-gamma and TGF-beta, and multiplex-immunohistochemistry. We expect to observe the synergistic inhibitory effect of LXR-623 and anti-PD1-Abs against chordomas through PD-L1 downregulation and reduction in immunosuppressive MDSC levels mediated by LXR-623. We plan to sacrifice the last animal group on August 24th. Due to the lengthy nature of the experiment (humanization and treatment take 13–14 weeks), the data are not fully available at the time of submission but will be available by the late-breaking deadline.