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Ann Oncol. 2020 Feb;31(2):266-273. doi: 10.1016/j.annonc.2019.11.002. Epub 2020 Jan 3.

Supporting clinical decision making in advanced melanoma by preclinical testing in personalized immune-humanized xenograft mouse models.

Author information

1
Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; Department of Oncology, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
2
Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
3
Department of Neurosurgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
4
Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: jonas.a.nilsson@surgery.gu.se.

Abstract

BACKGROUND:

The mouse strains usually used to generate patient-derived xenografts (PDXs) are immunocompromised, rendering them unsuitable for immunotherapy studies. Here we assessed the value of immune-PDX mouse models for predicting responses to anti-PD-1 checkpoint inhibitor therapy in patients.

PATIENTS AND METHODS:

Melanoma biopsies contained in a retrospective biobank were transplanted into NOG mice or NOG mice expressing interleukin 2 (hIL2-NOG mice). Tumor growth was monitored, and comparisons were made with clinical data, sequencing data, and current in silico predictive tools.

RESULTS:

Biopsies grew readily in NOG mice but growth was heterogeneous in hIL2-NOG mice. IL2 appears to activate T-cell immunity in the biopsies to block tumor growth. Biopsy growth in hIL2-NOG mice was negatively associated with survival in patients previously treated with PD-1 checkpoint blockade. In two cases, the prospective clinical decisions of anti-PD-1 therapy or targeted BRAF/MEK inhibitors were supported by the observed responses in mice.

CONCLUSIONS:

Immune-PDX models represent a promising addition to future biomarker discovery studies and for clinical decision making in patients receiving immunotherapy.

KEYWORDS:

NOG mice; immunotherapy; melanoma; mouse models; patient-derived xenografts

PMID:
31959343
DOI:
10.1016/j.annonc.2019.11.002
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