Data from: BLT-immune humanized mice as a model for nivolumab induced immune-mediated adverse events: Comparison of the NOG and NOG-EXL strains

Checkpoint inhibitors represent a new class of therapeutics in the
treatment of cancer that have 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 two 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 to 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 anti-PD1 therapy, and may represent a
model that can be used to better understand toxicity of this class of
drugs.