1. BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains.
- Author
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Weaver JL, Zadrozny LM, Gabrielson K, Semple KM, Shea KI, and Howard KE
- Subjects
- Animals, Bone Marrow Transplantation, Female, Genotype, Humans, Immune System immunology, Immune System metabolism, Immune System pathology, Liver Transplantation, Mice, Inbred NOD, Mice, Transgenic, Programmed Cell Death 1 Receptor immunology, Programmed Cell Death 1 Receptor metabolism, Signal Transduction, Species Specificity, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes pathology, Thymus Gland immunology, Thymus Gland transplantation, Antineoplastic Agents, Immunological toxicity, Immune System drug effects, Lymphocyte Activation drug effects, Nivolumab toxicity, Programmed Cell Death 1 Receptor antagonists & inhibitors, T-Lymphocytes drug effects
- Abstract
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-Prkdcscid Il2rgtm1Sug/JicTac (NOG) and NOD.Cg-Prkdcscid Il2rgtm1Sug 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., (Published by Oxford University Press on behalf of the Society of Toxicology 2019.)
- Published
- 2019
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