BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains

被引：28

作者：

Weaver, James L. ^{[1
]}

Zadrozny, Leah M. ^{[1
]}

Gabrielson, Kathleen ^{[1
,2
]}

Semple, Kenrick M. ^{[1
,3
]}

Shea, Katherine I. ^{[1
]}

Howard, Kristina E. ^{[1
]}

机构：

[1] US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 64,Room 2068, Silver Spring, MD 20993 USA

[2] Johns Hopkins Univ, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA

[3] US FDA, Div Gastroenterol & Inborn Errors Prod, Off Drug Evaluat 3, Off New Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

来源：

TOXICOLOGICAL SCIENCES | 2019年 / 169卷 / 01期

关键词：

checkpoint inhibitor; immune humanized mice; immunotoxicity; pharmaceuticals; histopathology; toxicity; chronic; CELL LUNG-CANCER; T-CELLS; CHECKPOINT INHIBITOR; HUMAN CD4(+); MOUSE; PD-1; ESTABLISHMENT; RESPONSES;

D O I：

10.1093/toxsci/kfz045

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

Checkpoint inhibitors represent a new class of therapeutics in the treatment of cancer that has demonstrated remarkable clinical effectiveness. However, some patients have experienced serious immune-mediated adverse effects including pneumonitis, hepatitis, colitis, nephritis, dermatitis, encephalitis, and adrenal or pituitary insufficiency. These adverse events were not predicted by nonclinical studies. To determine if bone marrow-liver-thymus (BLT) immune humanized mice could demonstrate these adverse effects, we studied the effect of nivolumab on 2 strains of BLT-humanized mice, NOD.Cg-Prkdc(scid) Il2rg(tm1Sug)/JicTac (NOG) and NOD.Cg-Prkdc(scid) Il2rg(tm1Sug) Tg(SV40/HTLV-IL3, CSF2) 10-7Jic/JicTac (NOG-EXL). Mice were treated with 2.5, 5.0, or 10.0 mg/kg nivolumab or saline twice weekly for 28 days. BLT-NOG mice had significantly reduced survival compared with BLT-NOG-EXL mice. In spite of the difference in survival, both BLT-humanized strains showed adverse reactions similar to those reported in humans, including pneumonitis and hepatitis, with nephritis, dermatitis and adrenalitis also noted in some individuals. Additional histopathologic findings included pancreatic atrophy, myositis, and osteomyelitis in some animals. T-cell activation increased with concomitant loss of PD-1 detection. These findings show that BLT immune humanized mice can demonstrate immune-mediated adverse effects of antiPD1 therapy, and may represent a model that can be used to better understand toxicity of this class of drugs.

引用

页码：194 / 208

页数：15

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