An explorative Study to Examine the Role of IL-23-Responsive Immune Cell Subsets in Post-Operative Recurrence in Patients with Crohn*s Disease

Inflammatory Bowel Diseases (IBDs), including ulcerative colitis and Crohn*s
disease (CD), constitute a group of debilitating chronic diseases that
profoundly impact patient quality of life and incurs large costs in terms of
treatment and lost productivity. Incidence of IBD is rising worldwide, and
there is a pressing clinical need for development of new therapies.
Discovery and development of effective therapies to treat IBDs depend first on
a better understanding of the underlying mechanisms, including how
proinflammatory cells proliferate unchecked.

It has been established that the cytokine interleukin (IL)-23 plays a pivotal
role in IBD pathophysiology and antibodies targeting IL-23 are currently in
late stage development for the treatment of both CD and ulcerative colitis
(UC). IL-23 is part of the IL-12 family of cytokines. The p40 subunit is
shared among IL-23 and IL-12; the p19 subunit is unique to IL-23. Thus far, the
efficacy of selective anti-IL-23 blockade (via anti-p19 antibodies) appears
5-10% better for clinical and endoscopic outcomes than targeting both IL-23 and
IL-12 using anti-p40 antibodies. Understanding the effects of IL-23 (and IL-12)
in IBDs requires identification of the most relevant immune cells that respond
to these cytokines.

One cell type strongly controlled by the IL-23 pathway are presumably the
innate lymphoid cells (ILCs). ILCs consist of 5 subsets: ILC1, ILC2, ILC3, NK
cells, and Lymphoid tissue inducer cells. These are relatively rare cells that
are strategically located in tissues to regulate innate immunity and tissue
homeostasis. Of these subsets, ILC3s are dominant in healthy intestinal tissue.
These cells are capable of producing IL-22 which maintain intestinal epithelial
homeostasis. The composition of ILCs in diseased tissues of CD patients
undergoing surgery is dramatically altered compared to normal tissue, which is
partly due to extensive plasticity of ILCs. ILC3s are capable of shifting into
high interferon (IFN)gamma-producing ILC1 in response to IL-12 produced by
intestinal macrophages. It is possible that IL-23 facilitates the IL-12-induced
shift to ILC1 which are contributing to the disease-causing chronic
inflammation, but this has yet to be investigated. Nonetheless, it is very
likely that this mechanism also plays a pivotal role in CD recurrence following
resectional surgery. Postoperative recurrence is observed in >80% of CD
patients undergoing resection. Other IL-23-responsive cell types including
Th17, mucosal-associated invariant T (MAIT) cells, and TCR-gammadelta-cells are
also present in the intestine but whereas Th17 cells are involved in IBDs in
experimental animal models, it is yet unknown whether these cells are involved
in pathology of CD.

Primary Objectives:
To unravel the immunological characteristics of postoperative recurrent CD and
study the immunological changes in the IL-23 pathway following treatment with
biological agents.

Secondary Objectives:
To study clinical, endoscopic and histological response to different treatments
given for postoperative CD.

This is an open-label, multi-center trial studying CD patients with
postoperative recurrence, diagnosed at ileocolonoscopy. Recurrence of CD is
defined by presence of ulcerations (endoscopic Rutgeerts* score >i2a) in the
neoterminal ileum.
We will take 8 biopsies at the baseline endoscopy (4 more than routine
practice) and 8 biopsies at the week 12-16 endoscopy. All biopsies will be
taken in areas of inflammation, in the proximity of (but not in the middle of)
ulcers. The number of biopsies taken is based on earlier experience on the
number of biopsies that is needed for reliable single cell read-out. Six
biopsies taken in the neoterminal ileum (edge of ulcerations) from the ileum
will be analyzed to identify immune cell populations of interest including rare
cells such as ILC and IL-23R positive immune cells, and two biopsies will be
used for Hematoxylin and eosin (H&E) staining and spatial transcriptomics.
Patients will be treated by their attending gastroenterologist and choice of
treatment will be determined by previous biologic agent exposure (as in routine
practice). Biological treatments that will be prescribed, are at the moment of
inclusion used in common IBD practice, which creates a heterogeneous group of
patients.

The intervention consists of the administration of a biological (guselkumab,
adalimumab or ustekinumab) that would also be given in routine practice. The
only exception to routine practice is the number of biopsies that will be taken
during endoscopy. Guselkumab has not been registered for Crohn's disease to
date (currently only for psoriasis), but will be registered for CD next year.

Patients will treated according to routine practice. It*s acceptable to expect
an effect from the started biological treatment. However, as in routine
practice, it*s possible that patients will not response to the therapy.
Participants will not have direct benefit from the data we collect by taking
biopsies and withdraw blood. However, with the data which we will retrieve from
this study we can explore the role of IL-23-responsive immune cell subsets in
CD-affected ileal resection tissue and post-operative recurrence.

Participants will undergo surgical resection and ileocolonoscopy as part of
their follow-up. Biopsy collections is part of routine clinical care and is not
associated with additional burden for the patient.