Abstract: TH-PO1142
Clinical Mitigation Strategies of Immune Checkpoint Inhibitor-Induced Nephrotoxicity Evaluated in a Humanized Mouse Model
Session Information
- Onconephrology: Emerging Biomarkers, Preclinical Models, Clinical Challenges, and Therapeutic Strategies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Asby, Sarah C., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
- Wen, Xia, Rutgers Ernest Mario School of Pharmacy Department of Pharmacology & Toxicology, Piscataway, New Jersey, United States
- Goedken, Michael J., Rutgers Ernest Mario School of Pharmacy Department of Pharmacology & Toxicology, Piscataway, New Jersey, United States
- Kostka-Newman, Zander C., University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Garcia, John Rhey Mhar G., University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Thekkumthala, Austin, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Lang, Julie, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Aleksunes, Lauren, Rutgers Ernest Mario School of Pharmacy Department of Pharmacology & Toxicology, Piscataway, New Jersey, United States
- Joy, Melanie S., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
Background
Immune Checkpoint Inhibitor (ICI)-induced nephrotoxicity is a clinically challenging adverse event managed empirically with corticosteroids or anti-TNFα drugs in steroid-refractory patients. However, the balance between mitigation of kidney injury and preserving antitumor efficacy remains poorly characterized. Human immune system (HIS) mouse models offer a clinically relevant platform for detecting and evaluating immunotoxicities. The purpose of this study was to evaluate the effects of methylprednisolone and infliximab on 1) ICI-induced kidney toxicity, and 2) antitumor efficacy in HIS mice.
Methods
Tumor-bearing (MDA-MB-231) non-humanized (BRGS) and humanized (HIS-BRGS) mice received nivolumab (20 mg/kg) + ipilimumab (10 mg/kg) weekly x4 doses. Mitigation drugs, methylprednisolone (1 mg/kg/day x7 days, i.p.) or infliximab (200 µg/week, i.p.) were administered at ICI doses 3 and 4 and compared to mice receiving only ICIs. Kidneys, spleen, lung, and tumor were analyzed by histopathology and flow cytometry.
Results
Renal vasculitis and interstitial nephritis were observed in ICI-treated HIS mice. The HIS mice receiving infliximab + ICI had reduced renal CD4+ GrB+ (5.6% vs 11.6%, p=0.047) and CD8+ GrB+ (77.2% vs 83.8%, p=0.042), and shifted renal CD8+ T cells from effector to central memory (Tem: 68.7% vs 78.4%, p=0.025; Tcm: 15.1% vs 11.2%, p=0.031) compared to ICI-only HIS mice. Both interventional drugs reduced renal CD8+ TIGIT+ (p<0.05) compared to ICI-only HIS mice, paradoxically indicating a more cytotoxic phenotype. Neither agent reduced the dominant renal CD4+ Tem population nor restored renal CD4+ Tregs. Infliximab treatment dramatically reduced tumor hCD45+ infiltration (22.3% vs. 58.6%, p<0.0001) compared to ICI-only HIS mice; however, there were no differences in tumor growth rates across groups.
Conclusion
Infliximab demonstrated broader attenuation of renal cytotoxic T cell activity than methylprednisolone; however, both agents paradoxically reduced the exhausted, less cytotoxic renal CD8+ TIGIT+ population compared to ICI treatment alone, suggesting incomplete mitigation. Suppression of tumor immune infiltration by infliximab raises concern for reduced antitumor immune activity of ICIs, warranting continued investigation.
Acknowledgment
All animal studies were conducted at the University of Colorado Animal Care Facilities. The Pre-clinical Human Immune System Mice Shared Resource (PHISM) at the University of Colorado generated and maintained the humanized mouse model and performed flow cytometry and analysis.
Funding
- Other NIH Support