The JAX® Onco-Hu® platform utilizes humanized mice engrafted with tumors to enable in vivo investigation of the interactions between the human immune system and human cancer. We have shown that humanized NOD-scid IL2Rγ null (NSG) mice bearing patient-derived xenografts (PDX) allow efficacy studies of checkpoint inhibitors. A major avenue of our investigation is to generate humanized mouse models containing a more complete human hematopoietic system and robust innate immune cell population. Nature killer (NK) cells are important players of innate defense against cancerous cells by a number of mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC). To overcome limited NK cell development in humanized NSG mice, we have developed NSG-Tg(Hu-IL15) (JAX stock number 030890) mice constitutively expressing human IL15. Following HSC-engraftment of NSG-Tg(Hu-IL15) mice, significantly higher levels of human CD16+CD56+ NK cells are detectable as compared to NSG mice in peripheral blood during the whole course of the study (18 weeks). Levels of circulating human CD45+ cells, CD3+ T cells, CD19+ B cells, and CD33+ myeloid cells are similar between the HSC-engrafted NSG-Tg(Hu-IL15) and NSG mice. Previously we have described that the human NK cells developing in HSC-engrafted NSG-Tg(Hu-IL15) mice are functional and can lyse the NK-sensitive target cells K562 by in vitro cytotoxicity assay. We also showed that NK cells limit the growth of a PDX melanoma xenograft. Here we show that humanized NSG-Tg(Hu-IL15) mice mediate efficient ADCC against Daudi B lymphoma cells in vivo. Administration of anti-human CD20 antibody (rituximab) resulted in significant tumor growth inhibition, in both tumor volume and tumor weight. We observed consistent ADCC efficacy in humanized NSG-Tg (Hu-IL15) mice engrafted with three different HSC donors. Together these data demonstrate that HSC-engrafted NSG-Tg(Hu-IL15) mice support enhanced development of functional human NK cells and that this mouse model enables NK cell-targeted cancer immunotherapy for preclinical testing.
Citation Format: Li-Chin Yao, Mingshan Cheng, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm, James G. Keck. Humanized NSG-Tg(Hu-IL15) mice support preclinical immune-oncology efficacy for testing of NK cell-based immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B72.