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

Journal article
Authors Lars Ny
Larissa Rizzo
Valerio Belgrano
Jón Karlsson
Henrik Jespersen
Louise Carstam
Roger Olofsson Bagge
Lisa M Nilsson
Jonas A Nilsson
Published in Annals of Oncology
Volume 31
Issue 2
Pages 266-273
ISSN 0923-7534
Publication year 2020
Published at Institute of Clinical Sciences, Department of Surgery
Institute of Clinical Sciences, Department of Oncology
Sahlgrenska Cancer Center
Institute of Clinical Sciences
Pages 266-273
Language en
Links dx.doi.org/10.1016/j.annonc.2019.11...
Keywords immunotherapy, melanoma, mouse models, NOG mice, patient-derived, xenografts, cd8(+) t-cells, metastatic melanoma, responses, therapy, disease, Oncology
Subject categories Cancer and Oncology

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.

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