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.

中文翻译：

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通过在个性化免疫人源化异种移植小鼠模型中进行临床前测试，支持晚期黑素瘤的临床决策。

背景技术通常用于产生患者源异种移植物（PDX）的小鼠品系具有免疫功能低下，使其不适用于免疫疗法研究。在这里，我们评估了免疫PDX小鼠模型对预测患者抗PD-1检查点抑制剂治疗反应的价值。患者和方法将回顾性生物库中包含的黑色素瘤活检样品移植到表达白介素2的NOG小鼠或NOG小鼠（hIL2-NOG小鼠）中。监测肿瘤的生长，并与临床数据，测序数据和当前的计算机预测工具进行比较。结果活检组织在NOG小鼠中易于生长，但在hIL2-NOG小鼠中生长是异质的。IL2似乎可以激活活检组织中的T细胞免疫，从而阻断肿瘤的生长。hIL2-NOG小鼠的活检生长与先前接受过PD-1检查点阻断治疗的患者的生存呈负相关。在两种情况下，观察到的小鼠反应支持了抗PD-1治疗或靶向BRAF / MEK抑制剂的前瞻性临床决策。结论免疫PDX模型代表了未来生物标志物发现研究的新希望，并有望为接受免疫治疗的患者提供临床决策。