Abstract A013: Preclinical case study: Patient-derived head and neck cancer xenograft on mice humanized with autologous immune cells, a model for personalized immuno-oncology research

Abstract

Abstract Background: The preclinical evaluation of novel immune modulators for cancer treatment remains a challenge, as models require both, engraftment of human tumor cells and a compatible human immune cell population. In previous experiments, we have demonstrated, that we can use either peripheral blood mononuclear cells (PBMC) or hematopoietic stem cells (HSC) to establish a humanized immune system with functional T-, B-, and NK cells, monocytes, and dendritic cells on highly immunodeficient mice. However these models are limited by rarely matching HLA isotypes between tumor and immune cells. In this case study, we established a patient-derived xenograft (PDX) model from a patient with head and neck squamous cell cancer (HNSCC). Furthermore, we collected blood samples and isolated PBMCs. After transplantation and engraftment of HNSCC PDX, patients PBMC were used to humanize mice. By this procedure we successfully generated a patient-specific human tumor-immune cell model in mice with 100% HLA-match. Model development included the comparison of PDX engraftment on mice with either HLA-matching or non HLA-matching PBMC’s from different donors. Finally, we further validated the model by comparing treatment effects with the checkpoint inhibitor Nivolumab in the autologous immune cell PDX model with the heterologous models. Methods: The HNSCC PDX HN15239 was transplanted on NOG mice. After tumor engraftment mice were randomized in 6 groups, receiving PBMCs by i.v. transplantation either from the patient or from 5 well characterized donors (PDX patient PBMCs – 100% HLA matching, 5 donors with different grade of HLA matching). Blood and tumor samples were analysed by FACS and IHC for immune cell infiltration and activation. Results:In the autologous huPBMC model, no interference with the proliferation of HN15239 PDX was seen. However, on mice humanized with donor PBMC’s with a high HLA match, a strong stimulation of tumor proliferation compared to non-humanized mice was observed. Surprisingly, treatment with Nivolumab did not induce a significant tumor growth inhibition in the autologous model system. On the mice humanized with PBMC from different donors, we observed a correlation of treatment effects with HLA match, with strong tumor growth inhibition in the mice with the best match. In the PDX tumors, infiltrating immune cells were detected by FACS and IHC analyses. Conclusions: We developed a humanized immune-PDX model enabling appropriate preclinical translational research on tumor immune biology and the evaluation of new therapies and combinations, as well as the identification and validation of biomarkers for immune therapy. Furthermore, results showed a correlation between immune therapy effect and HLA matching in preclinical models. Citation Format: Maria Stecklum, Konrad Klinghammer, Annika Wulf-Goldenberg, Bernadette Brzezicha, Korinna Jöhrens, Jens Hoffmann. Preclinical case study: Patient-derived head and neck cancer xenograft on mice humanized with autologous immune cells, a model for personalized immuno-oncology research [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A013. doi:10.1158/1535-7163.TARG-19-A013