Abstract 1697: Humanized immune-oncology mouse models

Abstract

Abstract The recent clinical success of immune checkpoint modulators has stimulated immune-oncology research leading to the identification of new tumor immunology targets. However both, target validation and drug development need better preclinical immune oncology models. Translational research further urgently needs such models for identification of clinically relevant biomarkers and defining rational combination strategies. 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 these mice lack a functional immune system, which allows tumor engraftment in the xenogenic host. To overcome these constraints our aim is the development of PDX models on mice with a functional human immune system. This strategy should allow implementing the highly predictable PDX in a functional human immune environment for better drug efficacy and safety studies. We reconstituted a human immune system in mice by engrafting human hematopoietic stem cells in immunodeficient mice. We demonstrate the engraftment of a full set of human immune cells, including T cells, B cells, NK cells, monocytes and dendritic cells in these mice. Tumor expression of PD-L1 is currently evaluated as first biomarker for immunotherapy with the PD1 checkpoint inhibitors. We screened our tumor cell lines and PDX models for PD-L1 expression to identify such a correlation. PD-L1 positive and negative models were transplanted on humanized mice. Most of them showed no difference in tumor growth compared to non-humanized mice (= fully immune resistant). However other PDX showed a delayed growth on the humanized mice (= partly immune resistant), whereas only one model did not grow at all (= immune sensitive), demonstrating a high sensitivity to the innate immune response of this PDX. To evaluate the function of the human immune cells and checkpoints, mice were treated with checkpoint inhibitors ipilimumab and nivolumab. Checkpoint inhibitors alone or in combination led to a minor tumor growth delay and an increased number of activated T-cells in the blood and in the tumor. Our results from experiments with n=19 models revealed a first correlation: stronger tumor growth inhibition on PD-L1 positive PDX and increased sensitivity of “partly immune resistant” PDX. Furthermore we were able to demonstrate, that treatment effects of checkpoint inhibitors could be increased by combination with radiation. Summary: Our humanized PDX models enable appropriate preclinical studies on tumor immune biology, evaluation of new immune therapies and combinations, as well as the identification and validation of biomarkers for tumor immune therapy. Citation Format: Maria Stecklum, Annika Wulf-Goldenberg, Bernadette Brzezicha, Iduna Fichtner, Jens Hoffmann. Humanized immune-oncology mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1697. doi:10.1158/1538-7445.AM2017-1697