Kidney Week

Abstract: SA-PO158

A Humanized Mouse Model as a Preclinical Tool to Evaluate Nephrotoxicity due to Cancer Immunotherapies

Session Information

• Onconephrology: Clinical and Research Advances - II
  November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Onconephrology

• 1600 Onconephrology

Authors

• Thompson, Lauren E., University of Colorado Health, Aurora, Colorado, United States

Lauren E. Thompson,

• Goedken, Michael J., Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States

Michael J. Goedken,

• Reuhl, Kenneth R., Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States

Kenneth R. Reuhl,

• Dominguez, Adrian Ta, University of Colorado Health, Aurora, Colorado, United States

Adrian Ta Dominguez,

• Pitts, Todd, University of Colorado Health, Aurora, Colorado, United States

Todd Pitts,

• Kiseljak-Vassiliades, Katja, University of Colorado Health, Aurora, Colorado, United States

Katja Kiseljak-Vassiliades,

• Aleksunes, Lauren, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States

Lauren Aleksunes,

• Lang, Julie, University of Colorado Health, Aurora, Colorado, United States

Julie Lang,

• Joy, Melanie S., University of Colorado Health, Aurora, Colorado, United States

Melanie S. Joy,

Background

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer by targeting inhibitory receptors on tumor and T cells. However, post-marketing surveillance has demonstrated that these therapies cause immune-mediated adverse events including nephrotoxicity. We evaluated a mouse model with a humanized immune system as a preclinical and translational tool to identify kidney toxicities in response to cancer immunotherapies.

Methods

Three feasibility studies were conducted in newborn BALB/c-Rag2^nullIl2ry^nullSirpα^NOD (BRGS; nonhumanized) mice which were irradiated and injected with CD34+ hematopoietic cells isolated from human umbilical cord blood to generate mice with a humanized immune system (HIS-BRGS). After 2 weeks of tumor growth followed by 2-4 weeks of ICI treatment (Table 1), H&E-stained sections of kidneys from the mice were analyzed for histomorphological evidence of injury. Incidence and severity scores (range of 0 to 3) were recorded. Statistical analyses were conducted using rank order one-way ANOVAs with Tukey-Kramer post-hoc tests (R).

Results

Humanization of the immune system caused minimal glomerulonephritis (p<0.0001) in all HIS-BRGS mice compared to BRGS mice. Compared to vehicle-treated HIS-BRGS mice, treatment with nivo/ipi trended towards worsening glomerulonephritis (p=0.056). Nivo alone, as well as nivo/ipi, resulted in interstitial nephritis (nivo: p=0.016, ipi/nivo: p=0.004) and periarteritis (nivo: p=0.027, ipi/nivo: p=0.003) in HIS-BRGS mice compared to vehicle-treated HIS-BRGS mice. Pembro/mito- and pembro/cetux/CD-47 antagonist-treatment resulted in increased periarteritis compared to vehicle-treated and single agent-treated HIS-BRGS mice (pembro/mito: p=0.042, pembro/cetux/CD-47 antagonist: p=0.090).

Conclusion

Humanized HIS-BRGS mice represent a highly innovative and promising preclinical and translational model to evaluate immune-related kidney toxicities including glomerulonephritis, periarteritis, and interstitial nephritis from ICIs.

Funding

• Other NIH Support