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

Weaver, James L, United States Food and Drug Administration

Zadrozny, Leah M, United States Food and Drug Administration

Gabrielson, Kathleen, United States Food and Drug Administration

Semple, Kenrick M, United States Food and Drug Administration

Shea, Katherine I, United States Food and Drug Administration

Howard, Kristina E, United States Food and Drug Administration

Published Jan 23, 2019 on Dryad. https://doi.org/10.5061/dryad.99fq552

Cite this dataset

Weaver, James L et al. (2019). Data from: BLT-immune humanized mice as a model for nivolumab induced immune-mediated adverse events: Comparison of the NOG and NOG-EXL strains [Dataset]. Dryad. https://doi.org/10.5061/dryad.99fq552

Abstract

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.

Usage notes

Suppl Table 1

Summary of histopathologic findings for each animal.

Supplemental Figure 1

Supplemental Figure 1: Spleen and submandibular lymph node pathology. Splenic (left panel) and lymph node (right panel) sections considered to have normal parenchymal architecture from a saline control BLT-NOG mouse are shown in A and B respectively. In BLT-NOG (C) and BLT-NOG-EXL (E) nivolumab treated mice, multifocal, pale, expansile nodules composed mainly of histiocytes (insets) were observed. Similarly, lymph nodes in the BLT-NOG (D) and BLT-NOG-EXL (E) treated groups exhibited histiocytic nodular infiltrates (high magnification insets) that were slightly more eosinophilic. Hematoxylin and eosin.

Supplemental Figure 2

Supplemental Figure 2: Pathology of less common histological findings in BLT-NOG and BLT-NOG-EXL nivolumab treated mice. Lesions observed in both BLT-NOG and BLT-NOG-EXL treated mice included submucosal lymphohistiocytic infiltrates in the stomach (A), often at the region of the limiting ridge, and; regionally extensive, mural to transmural lymphohistiocytic and neutrophilic infiltrates in the cecum (B). Lesions limited to BLT-NOG-EXL nivolumab treated mice included multifocal lymphocytic (and fewer histiocytic) infiltrates in the urinary bladder submucosa (C); mild, regionally extensive lymphocytic meningitis at the level of the diencephalon (D), and; multifocal lymphohistiocytic and occasionally neutrophilic infiltrates extending into the trigeminal nerve and ganglia (E), and the pituitary gland (F). Hematoxylin and eosin.

Supplemental Figure 3

Supplemental Figure 3: Representative histological figures from a mouse with graft versus host disease. GvHD inflammatory lesions in skin (A), lung (B), liver (C), kidney (D), pancreas (E), and sternum (F) are considered less severe, segmental to multifocal rather than more diffuse, and consist of more lymphocytes than histiocytes (insets) with fewer instances of granulomas compared to nivolumab treated BLT-NOG and BLT-NOG-EXL mice. Hematoxylin and eosin.

Location

Maryland