To determine mechanisms behind immune checkpoint blockade-related adverse effects (irAE) in melanoma, Bauché et al. developed a mouse model of anti-CTLA-4-mediated enterocolitis. Sustained injections of Fc-competent anti-CTLA-4 (Fc-effector), but not Fc-mutant or Fc-null versions, drove intestinal irAE, suggesting that FcγR engagement is required. Only Fc-effector anti-CTLA-4 monotherapy was effective in tumor models, whereas in combination with anti-PD-1, Fc mutant or Fc-null CTLA-4 antagonists also drove potent antitumor efficacy, suggesting that antitumor efficacy without intestinal inflammation may be possible.
Contributed by Katherine Turner
BACKGROUND: Programmed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events. METHODS: We have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody. RESULTS: Sustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit. CONCLUSION: These data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.