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JAK1 BLOCKADE AMELIORATES DISEASE SEVERITY IN IMMUNE CHECKPOINT INHIBITOR-INDUCED COLITIS

Jonathan Lo 1, Hajir Ibraheim 1, Marton Olbei 1, Balazs Bohar 1, John Thomas 1, Tamas Korcsmaros 1, Domenico Cozzetto 1, Nick Powell 1

Affiliations

1 Imperial College London, London, United Kingdom

Summary

AI Generated

IFNγ/JAK1 signalling is upregulated in immune checkpoint inhibitor-induced colitis, and JAK1 inhibition with Upadacitinib ameliorated disease in preclinical models and achieved complete mucosal healing in eight treatment-refractory patients.

Gene expression profiling of colonic biopsies from CPI-colitis patients identified IFNγ signalling as the top enriched pathway, with IFNγ-responsive transcripts including CXCL9, CXCL10, IDO1, GZMB and STAT1 among the most upregulated.
In two murine models of CPI-colitis, Upadacitinib administration significantly reduced colon mass, infiltrating neutrophils, inflammatory monocytes, and CD8+ T cells producing cytotoxic cytokines.
Colonic organoids from CPI-colitis patients expressed high baseline IFNγ-responsive transcripts and showed destruction when treated with IFNγ alone, but survived and showed continued differentiation when co-treated with Upadacitinib.
All eight patients with severe, treatment-refractory CPI-colitis treated with Upadacitinib 45mg for eight weeks achieved rapid resolution of disease, complete mucosal healing, and significant decreases in CTCAE grade and faecal calprotectin.
This work is relevant to clinicians managing patients with severe or refractory immune checkpoint inhibitor-induced colitis.

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Immune checkpoint inhibitors (CPI) have revolutionised cancer outcomes, but frequently trigger immune related adverse effects, including life-threatening colitis. Current immunosuppressive treatments for CPI-colitis (CPI-C) incur significant side effects and may compromise CPI efficacy, highlighting the constant need for new therapies.

Aims & 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. The impact of JAK1 blockade was evaluated in vivo using our pre-clinical model of CPI-C. Clinical readouts and colonic leukocytes were analysed by flow cytometry. Colonic organoids from CPI-C and controls were cultured and treated with IFNγ ± JAK1 inhibition with Upadacitinib. Clinical and endoscopic outcomes were defined in patients with treatment-refractory CPI-C following treatment with Upadacitinib 45mg for 8 weeks. Finally, we used a novel humanised mouse model of CPI-C, whereby mice express the human CTLA4 and PD1 gene, to validate these patient findings. Mice were given Nivolumab (6mg/kg) and Ipilimumab (10mg/kg) every 3 days with and without treatment of Upadacitinib (10mg/kg) and clinical features and flow cytometry were used to assess disease severity in these mice.

Results

Gene expression profiling of colonic biopsies highlighted overactivity of the JAK1-dependent cytokine IFNγ in CPI-C. IFNγ-responsive transcripts, including CXCL9, CXCL10, IDO1, GZMB and STAT1, were among the most upregulated transcripts, with IFNg signalling identified as the top enriched pathway. In vivo administration of Upadacitinib significantly reduced pathological clinical features, with reduced colon mass and infiltrating neutrophils, although no changes in T cell cytokine responses were seen in mice treated with CPI-C. Colonic organoids from CPI-C patients expressed high baseline expression of IFNγ-responsive transcripts and significantly overexpressed these transcripts following ex vivo stimulation with IFNγ, which was corroborated at protein level. Upadacitinib treatment of stimulated organoids were able to dampen these responses. To examine the functional impact of the IFNg/JAK1 pathway in CPI-colitis we blocked IFNg (neutralizing mAbs) or JAK1 (Upadacitinib treatment) in a humanised CTLA4 and PD1 murine model of CPI-colitis, which significantly attenuated disease with reduction in colon mass and fewer infiltrating neutrophils and fewer inflammatory monocytes. Humanised mice treated with Upadacitinib also had fewer CD8⁺ T cells in the colonic lamina propria, which also produced less cytotoxic cytokines. Encouraged by these findings, we treated 8 patients with severe, treatment refractory CPI-C with Upadacitinib. All achieved rapidly resolution of disease and complete mucosal healing.

Conclusion

IFNγ/JAK1 signalling was upregulated in CPI-C patients, which was recapitulated in a novel CPI-C derived colonic organoid model and two in vivo models of disease. Upadacitinib improved organoid morphology, reduced IFNγ 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.W., Cozzetto, D., Alexander, J.L. et al. Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis. Nat Commun 14, 6719 (2023). https://doi.org/10.1038/s41467-023-41798-2
2. Luoma A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655-671.e22 (2020).
3. Sasson, S. C. et al. Interferon-gamma-producing CD8(+) tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis. Gastroenterology 161, 1229–1244.e1229 (2021).
4. Gupta T, Antanaviciute A, Hyun-Jung Lee C, et al. Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis. Cancer Cell. 2024 May 13;42(5):797-814.e15. doi: 10.1016/j.ccell.2024.04.010. PMID: 38744246.

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

Colorectal cancer: Working around genetics and complications (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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