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

James L. Weaver, Leah M. Zadrozny, Kathleen L Gabrielson, Kenrick M. Semple, Katherine I. Shea, Kristina E. Howard

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)194-208
Number of pages15
JournalToxicological sciences : an official journal of the Society of Toxicology
Volume169
Issue number1
DOIs
StatePublished - May 1 2019

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Thymus
Liver
Thymus Gland
Bone
Bone Marrow
Dermatitis
Nephritis
Hepatitis
Pneumonia
Adrenal Insufficiency
Hypopituitarism
Inbred NOD Mouse
Myositis
T-cells
Survival
Encephalitis
Osteomyelitis
Colitis
Drug-Related Side Effects and Adverse Reactions
Atrophy

Keywords

  • checkpoint inhibitor
  • chronic
  • histopathology
  • immune humanized mice
  • immunotoxicity
  • pharmaceuticals
  • toxicity

ASJC Scopus subject areas

  • Toxicology

Cite this

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.; Zadrozny, Leah M.; Gabrielson, Kathleen L; Semple, Kenrick M.; Shea, Katherine I.; Howard, Kristina E.

In: Toxicological sciences : an official journal of the Society of Toxicology, Vol. 169, No. 1, 01.05.2019, p. 194-208.

Research output: Contribution to journalArticle

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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.",
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