Abstract 5200: Preclinical model of patient-derived tumor xenograft in humanized mice

Abstract

Abstract Human patient-derived xenografts (PDX) from different tumor indications transplanted on immunodeficient mice have demonstrated strong predictive power for many drug development programs in cancer research. However, one caveat of PDX models is that they lack a functional immune system, which allows tumor engraftment in the xenogenic host mice. Immunotherapy has emerged as one of the most promising avenues for cancer therapy. For translating immunotherapies into the clinics preclinical animal models are needed which harbor human immune cell repertoire for rising an immune response. To overcome these constraints our aim is the development of PDX models on mice with a functional human immune system to improve predictability of drug efficacy and safety. We reconstituted a human immune system in mice by engrafting human hematopoietic stem cells in immunodeficient mice. We were able to demonstrate that in the mice a full set of human immune cells, including T cells, B cells, NK cells, monocytes and dendritic cells can be analyzed by flow cytometry. At the time when the human immune system was developed, established patient-derived tumors were transplanted on these reconstituted humanized mice. PDX from different tumor entities were transplanted. The tumors are growing on these humanized mice either similar to non humanized mice or slightly slower. During the observation period no rejections by the human immune cells were evident, although tumor growth was accompanied by an increase of human T cells in the peripheral blood. Ex vivo analysis will be performed demonstrating the cytotoxicity of these T cells and the functionality of the human immune cells. Humanized mice bearing various PDX tumors were treated with therapeutic checkpoint inhibitors. Ipilimumab that target the CTLA-4 receptor lead to a slight tumor growth delay and an increased percentage of T cells in the blood and in the tumor. Nivolumab that targets the PD-1 receptor showed similar results. The combination of both inhibitors showed a synergistic effect which lead to a greater tumor growth inhibition. Our humanized mouse models enable appropriate preclinical assessment of immune-based therapeutic anti-tumor strategies especially when combing the humanized mouse with patient-derived tumor xenografts. Citation Format: Annika Wulf-Goldenberg, Maria Stecklum, Iduna Fichtner, Jens Hoffmann. Preclinical model of patient-derived tumor xenograft in humanized mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5200.