A double humanized mouse model of immune checkpoint blockade to study immune-related adverse events due to cancer immunotherapy 3957

Abstract Description Immune checkpoint blockade (ICB) therapies, including anti-CTLA4 (ipilimumab) and anti-PD1 (pembrolizumab), have revolutionized cancer treatment by reinvigorating antitumor immunity. However, ICB therapies often cause immune-related adverse events (irAEs), off-target toxicities limiting clinical utility. Current models, like single humanized CTLA-4 (hCTLA4) knock-in mice, provide insights into ICB biology but fail to fully replicate the multi-organ inflammation seen in patients. Moreover, ipilimumab monotherapy does not mimic the complexity of irAEs from combination therapies. To address these gaps, we developed a double humanized immune checkpoint knock-in (hCTLA4/hPD1) mouse model to study ICB-driven irAEs in solid tumor. This model supports ipilimumab and pembrolizumab, replicating human ICB regimens and enabling evaluation of therapeutic efficacy and adverse effects in the tumor microenvironment. Immunotherapy-prone tumor models were integrated into hCTLA4/hPD1 mice to assess systemic and tumor-specific immune responses to combination ICB. Using this model, we are exploring bioactive lipids, identified by our group, that mitigate ICB-driven irAEs in single hCTLA4 knock-in mice. This double-knock-in model bridges gaps between preclinical ICB models and human irAEs, enabling mechanistic studies of irAEs under clinically relevant regimens. It also facilitates testing interventions like lipid supplementation, advancing safer, more effective immunotherapies. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)