PO-218 Cytokine-transgenic NOG mice engrafted with human peripheral blood cells support natural killer cell expansion

Introduction Given the central role natural killer (NK) cells exert in immune responses and the great therapeutic potential they hold due to their ability to mediate antibody-dependent cellular cytotoxicity (ADCC), it is necessary to optimise available preclinical models for ongoing immuno-oncology efforts. Currently, most preclinical in vivo studies of ADCC-dependent efficacy rely on syngeneic models, which mandate the generation and use of surrogate therapies to overcome differences between mouse and human immune systems. Human NK cell-dependent cancer therapies could profit from a humanised immune system (HIS) model that supports human NK cells. However, so far HIS models have largely failed to support human NK cell-engraftment, rendering them inadequate for ADCC studies. Recent work with human cytokine-transgenic hIL-2 NOG and hIL-15 NOG mice showed that the development of human NK cells from engrafted human hematopoietic stem cells (HSCs) is favoured. If hIL-2 NOG and/or hIL-15 NOG mice might also be suited to support NK cells after engraftment of peripheral blood mononuclear cells (PBMCs) remains to be investigated. NK cell maintenance after engraftment of PBMCs would make a cost-effective and efficient model for in vivo studies of human NK cells and therapeutic human antibodies. Material and methods To test this hypothesis, CIEA NOG mouse ® (NOG), hIL-2 NOG, and hIL-15 NOG mice were engrafted with PBMCs from a single donor and at one of three increasing cell doses. The onset of graft vs host disease and peripheral blood human immune cell subsets were monitored for several weeks. Results and discussions Results showed that hIL-15 NOG mice had a slightly diminished survival compared to conventional NOG. Nevertheless, hIL-15 NOG survived up to 7 weeks after PBMC engraftment without any signs of graft vs host disease. Although hIL2-NOG mice showed the best engraftment rate for NK cells and other immune cell subpopulations, the overall survival was severely decreased post engraftment. Comparing NK cell-engraftment in hIL-15 NOG and conventional NOG mice, we observed a tenfold increase of NK cell numbers in hIL-15 NOG mice independent of engrafted PBMC numbers. Conclusion Results suggest that hIL-15 NOG mice engrafted with PBMCs make a highly suitable HIS model for studying NK cell activity.