DOP067 Selective JAK1 blockade with Upadacitinib is effective in immune checkpoint inhibitor-induced colitis
Authors: Ibraheim H , Cozzetto D , Olbei M , Thomas J P , Korcsmaros T , Lo J W , Powell N 
Published: January 2025

Abstract

Background
Immune checkpoint inhibitors (CPI) have transformed cancer outcomes, but frequently trigger autoimmune- like events, including life-threatening colitis. Current immunosuppressive treatments for CPI- colitis (CPI-c) incur significant side effects and may compromise CPI efficacy, highlighting the need for new therapies.

Methods
RNA sequencing was performed on colonic biopsies from patients with CPI-c (n=12), CPI (no colitis, n=6), healthy controls (n=13), and UC (n=12). Gene expression, pathway level (GSEA) and cellular composition were analysed. Cell-cell communication were analysed using a single-cell RNA sequencing reposited dataset. Colonic organoids from CPI-c and controls were cultured and treated with IFNg ± JAK1-STAT inhibition with Upadacitinib . The impact of JAK1 blockade was evaluated in vivo using pre-clinical models of CPI-c1. Colonic leukocytes were analysed by flow cytometry. Clinical and endoscopic outcomes were defined in five patients with treatment-refractory CPI-c, following treatment with Upadacitinib 45mg for 8 weeks.

Results
Gene expression profiling of colonic biopsies highlighted overactivity of the JAK1-dependent cytokine IFNg in CPI-c. IFNg responsive transcripts, including CXCL9, CXCL10, IDO1, GZMB and STAT1, were among the most upregulated transcripts, with IFNg signalling identified as the top enriched pathway. Cellular deconvolution revealed enrichment of TH1 and CD8+ memory cells. Cell-cell communication analysis indicated distinct dialogue mediated by IFNg between T-cell subsets in CPI-c, including TH17+PD1+ and epithelial cells, and inflammatory enterocytes. Colonic organoids from CPI-c patients retained high baseline expression of IFNg-responsive transcripts, and significantly over-expressed these following ex vivo stimulation with IFNg, which was corroborated at protein level. Upadacitinib treatment of stimulated organoids reversed these changes. In vivo administration of Upadacitinib significantly reduced pathological features and severity of CPI-c in preclinical models of disease. Encouraged by these findings, we treated 5 patients with severe, treatment refractory CPI-c with Upadacitinib. All achieved rapidly resolution of disease with complete mucosal healing, no adverse events, and favourable 9-month cancer outcomes were sustained.

Conclusion
IFNg signalling was highly upregulated in CPI-colitis patients, which was recapitulated in a novel CPI-c derived colonic organoid model and in vivo models of disease. Upadacitinib improved organoid morphology, reduced IFNg targets, and ameliorated CPI-c in mice. Moreover, Upadacitinib rapidly rescued treatment refractory patients highlighting its potential as a promising therapeutic approach in patients with severe disease.

References
1. Lo J, Cozzetto D, Liu Z, et al. Immune checkpoint inhibitor-induced colitis is mediated by CXCR6+ polyfunctional lymphocytes and is dependent on the IL23/IFNγ axis. Nat Commun. 2022;13(1)41798. doi:10.1038/s41467-023-41798-2