Abstract B72: Humanized NSG-Tg(Hu-IL15) mice support preclinical immune-oncology efficacy for testing of NK cell-based immunotherapy

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. 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) mice constitutively expressing human IL15 in a physiological level. Following CD34+ HSC-engraftment of NSG-Tg(Hu-IL15) mice, significantly higher levels of human NK cells are detectable in peripheral blood as compared to NSG mice and the engraftment is stable for over six months. Levels of circulating human CD45+ cells, CD3+ T cells, and CD33+ myeloid cells are similar between the HSC-engrafted NSG-Tg(Hu-IL15) and NSG mice. Minimal baseline activation of NK cells is detected in the spleen and peripheral blood. 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 directly limited growth of a PDX melanoma xenograft and NK cell depletion by antibody blockage largely abrogated the delayed PDX growth. Here we extended these observations by evaluating tumor growth of multiple PDX and CDX models in humanized NSG-Tg(Hu-IL15) mice. We found that not all tumors were able to grow and for those that grew some spontaneous regression might still occur. In ex vivo experiments NK cells in the PBMCs isolated from humanized NSG-Tg(Hu-IL15) mice could be activated by Her2+ human cancer cells in the presence of anti-human H2 antibody (Trastuzumab). Furthermore we showed in vivo that humanized NSG-Tg(Hu-IL15) mice mediated efficient ADCC against Daudi B lymphoma cells using anti-human CD20 antibody (Rituximab). Administration of rituximab resulted in significant tumor growth inhibition as measured by both tumor volume and tumor weight. 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 preclinical evaluation of NK cell-targeted cancer immunotherapy in vivo. Citation Format: Li-Chin Yao, Mingshan Cheng, Danying Cai, Leonard D. Shultz, James G. Keck. Humanized NSG-Tg(Hu-IL15) mice support preclinical immune-oncology efficacy for testing of NK cells based immunology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3320.