Abstract A006: Preclinical tumor models in humanized mice for translational immuno-oncology research

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 require appropriate humanized preclinical models. Translational research further urgently needs such models for identification of clinically relevant biomarkers and defining rational combination strategies. In previous studies, we have demonstrated that hematopoietic stem cells (HSC) can proliferate and differentiate in immunodeficient mice and establish a functional human immune system with T cells, B cells, NK cells, monocytes, and dendritic cells. Further, we have shown engraftment of patient- (PDX) and cellline-derived xenografts (CDX) on these humanized mice. All CDX and most of the PDX showed no difference in tumor growth compared to non-humanized mice (fully immune resistant). However, some PDX showed a delayed tumor growth on the humanized mice (partly immune resistant), whereas only one model did not grow at all (immune sensitive). This model is demonstrating the functionality of the established human immune system against a PDX. In the next step, we determined PD-L1 expression on different CDX and PDX on RNA and on protein level. Engraftment seems to be dependent on PD-L1 expression on the PDX, with a higher PD-L1 expression correlating with a stronger tumor growth delay. In the last step the PDX/humanized mice system was evaluated for response to the treatment with checkpoint inhibitors alone and in combination therapy with radiation. So far we treated over 20 PDX and CDX models (lung, colon, melanoma, mammary, ovarian, lymphoma) with ipilimumab, nivolumab, and radiation. In most cases we observed a slight tumor growth delay and increased numbers of T cells in the blood and in the tumor. In our fully humanized model system we identified a correlation between response to checkpoint inhibitor treatment and PD-L1 expression on the PDX or CDX. These results demonstrate that fully 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 immune therapy. Citation Format: Maria Stecklum, Annika Wulf-Goldenberg, Magdalena Paterka, Bernadette Brzezicha, Iduna Fichtner, Jens Hoffmann. Preclinical tumor models in humanized mice for translational immuno-oncology research [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A006.