Simulated CD8+ T Cell-Mediated Liver Injury During Ipilimumab Administration in a Simulated Population (SimPops®) Demonstrates Profiles Consistent with Observed Clinical Data

Authors: Sandefur CI, Clemens L, Kelley MR, Beaudoin J, Battista C, Siler SQ, Shoda LKM, Howell BA, Yang K
Conference: ACoP
Keywords: alanine aminotransferase (ALT), BIOLOGXsym, immune checkpoint inhibitors, ipilimumab, SimPops, T cell-mediated liver injury
Software: BIOLOGXsym
Division: Quantitative Systems Pharmacology (QSP)

Objective

Immune checkpoint inhibitors (ICIs) have revolutionized treatment of various cancers. They act by releasing the brakes on immune responses to permit immune-mediated tumor cell killing. Many ICIs are also associated with immune-related adverse events (irAEs), including liver injury. Of patients treated with the ICI ipilimumab, 7% exhibit signs of liver injury, e.g., alanine aminotransferase (ALT) elevations. Ipilimumab targets CTLA-4, an inhibitory cell surface protein expressed on activated T cells. One hypothesis for ipilimumab-mediated liver injury is that CTLA-4 inhibition is permissive for normally suppressed de novo T cell responses to liver antigens. We applied a quantitative systems toxicology (QST) model of biologics-mediated liver injury (BIOLOGXsym™) to investigate this hypothesis.

Methods

  • BIOLOGXsym represents liver parenchymal and nonparenchymal cell dynamics, such as innate and adaptive immune responses. The modeled adaptive immune response leverages CD8+ T cell responses specific for hepatocyte-expressed antigen as previously described.
  • Ipilimumab was modeled as inhibiting early regulatory signaling in the T cell activation cascade, leading to a net increase in T cell avidity for hepatocyte-expressed antigen and aberrant expansion of hepatocyte specific CD8+ T cells.
  • Variability in ipilimumab pharmacokinetics, patient anthropometric characteristics, and liver biochemistry were not included.

Conclusion

The undeniable benefit of ICIs is tempered by the risk of irAEs, which are poorly understood and therefore difficult to avoid. These results provide an initial demonstration of how QST can be applied to explore mechanistic hypotheses and identify key drivers of ICI liver injury. Further, these results set the stage for collaborations to generate additional data to inform key parameters, confirm/refute assumptions, and improve our understanding of these important safety concerns. Supported by NIH-R44TR003535.

By Conner Sandefur, Lara Clemens, Michael Kelley, James J. Beaudoin, Christina Battista, Scott Q. Siler, Lisl K.M. Shoda, Brett A. Howell, Kyunghee Yang

Fifteenth American Conference of Pharmacometrics (ACoP15), November 10-13, 2024, Phoenix, Arizona