Harnessing natural killer (NK) cells and their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) forms the basis for many 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. These steps add time and cost, and can be particularly challenging for advanced antibody therapeutics (e.g. bispecific antibodies and antibody-drug conjugates). A humanized immune system (HIS) model that supports human NK cells could improve evaluations of human NK cell-dependent cancer therapies. However, HIS models have largely failed to support human NK cell-engraftment, rendering them inadequate for ADCC studies. Prior work has shown that human cytokine-transgenic hIL2-NOG and hIL15-NOG mice support the development of human NK cells from engrafted human hematopoietic stem cells (HSCs). Furthermore, the hIL15-NOG model has been shown to support in vivo expansion and long-term engraftment of isolated human NK cells. These properties suggest hIL2-NOG and/or hIL15-NOG might also sufficiently support NK cells following engraftment of peripheral blood mononuclear cells (PBMCs). Such a model could enable cost-effective and efficient in vivo studies of human NK cells and therapeutic human antibodies. To test this hypothesis, 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 through the duration of this study. Results showed that hIL15-NOG mice had a slightly diminished survival compared to conventional NOG. Nevertheless, hIL15-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 hIL15-NOG and conventional NOG mice, we observed a tenfold increase of NK cell numbers in hIL15-NOG mice, independent of engrafted PBMC numbers, making it a highly suitable HIS model for studying NK cells.

Citation Format: Paul Volden. Cytokine-transgenic NOG mice engrafted with human peripheral blood cells support natural killer cell expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-088.