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Stecklum, Maria; Wulf-Goldenberg, Annika; Brzezicha, Bernadette; Klinghammer, Konrad; Jöhrens, Korinna; Walther, Wolfgang; Hoffmann, Jens
Cancer research, 07/2021, Letnik: 81, Številka: 13_SupplementJournal Article
Abstract Background: The preclinical evaluation of novel immune checkpoint modulators is dependent on models with functional human immune cells. 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 on highly immunodeficient mice with functional T, B or NK cells. Furthermore, we determined PD-L1 expression as a predictive marker and target for immunotherapy on different patient-derived xenografts (PDX). By co-transplantation of PDX, we successfully generated a fully human tumor-immune-cell model in mice. Finally, we evaluated the functionality of the model by the treatment with checkpoint inhibitors and for combination therapies i.e. with chemotherapy or radiation. Methods: HSC-humanized mice (HIS) were generated by i.v. transplantation of HSC. Engraftment of immune cells was monitored by FACS analysis. For PBMC-humanized mice, immune cells were implanted i.v. PD-L1 expression on PDX was determined by FACS and immunohistochemistry (IHC). PDX from 13 different entities (i.e. melanoma, lymphoma) were transplanted on HIS mice and treated with Ipilimumab (Ipi) and Nivolumab (Nivo) alone or in combination with radiation. Results: 14 weeks after HSC transplantation up to 20% of the human immune cells in the blood were T-cells. We have transplanted more than 40 different PDX from 13 different tumor entities on HIS mice. Most of the investigated PDX (>70%) successfully engrafted and showed no significant difference in tumor growth compared non-humanized mice. However, for some PDX we observed a delayed tumor growth or a complete rejection. Engraftment delay seems to correlate with the PD-L1 expression of PDX (the higher PD-L1, then the higher growth delay). Treatment with Ipi or Nivo alone or in combination led to a minor tumor growth delay and an increased percentage of T-cells in the blood and the tumor. Response showed a correlation to innate immune response and PD-L1 expression of PDX and could further be increased by combination with radiotherapy. Conclusions: Our humanized immune-PDX models enable 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. Citation Format: Maria Stecklum, Annika Wulf-Goldenberg, Bernadette Brzezicha, Konrad Klinghammer, Korinna Jöhrens, Wolfgang Walther, Jens Hoffmann. Preclinical models for translational immuno-oncology research: patient-derived xenografts on humanized mice abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2713.
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Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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