Immune checkpoint blockade and autoimmune diseases: Development of a mouse model of colitis induced by anti-CTLA-4

Immunotherapies prime or activate patient’s immune system to fight disease and has recently been a source of registered and promising new cancer treatments with major beneficial clinical outcomes in several cancers. However, by increasing the activity of the immune system, therapies as such targeting the immune checkpoint blockade can have profound inflammatory side effects, termed immune-related adverse events, with particular organs affected such as gastrointestinal tract, endocrine glands, skin and liver. In patients treated with the anti-CTLA-4 antibody, Ipilimumab, the overall incidence of diarrhea and colitis has been reported as 32.8%. This side effect is also observed in patients treated with anti-PD-1 therapy. The reproduction of such aspects of immune checkpoint inhibitors side effects in preclinical animal models would serve to dig into deciphering mechanisms involved, but also to evaluate combination therapies and modalities to reduce and manage such incidence with potential beneficial translation in clinical practice. We thus first ought to establish a checkpoint blockade-related autoimmune mouse model of colitis, using female C57BL/6 mice which were tested to determine their response to orally administered dextran sulfate sodium (DSS) combined to multiple injections of anti-CTLA-4 antibody or an isotype control antibody. After administration of DSS in drinking water for 7 days, mice that received an anti-CTLA-4 antibody showed no difference in body weight loss and Disease Activity Index (composite of body weight loss, stool consistency and presence of blood in stools), when compared to mice that received DSS plus the isotype control antibody. Histological sections analysis from the colons of mice culled at Day 10 confirmed that the combined treatment did not change the colitis score.However, when looking at later time points corresponding to the usual recovery phase of colitis, the effect of anti-CTLA4 treatment was clearly revealed by a sustained body weight loss and the persistence of a high Disease Activity Index, while the isotype control-treated animals slowly returned to baseline values similar to untreated animals. At sacrifice on Day 19, these in life findings were confirmed by a decrease in colon length (- 0.94 cm), an increase in colon weight (+ 231 mg) and a high mucus colon production in the anti-CTLA4-treated group versus the isotype control-treated group. Histological analysis of colons, and a more in depth characterization of the immune infiltrates will be presented. Citation Format: Edwige Nicodeme, Florence Blandel, Valerie Boullay, Yannick Saintillan, Gael Krysa, Anne-Benedicte Boullay, Jean-Jacques Tousaint, Robin Artus, Laure Levenez, Jeremy Odillard, Ingrid Jacquet, Olivier Duchamp, Fabrice Viviani. Immune checkpoint blockade and autoimmune diseases: Development of a mouse model of colitis induced by anti-CTLA-4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3228.