Decoding predictors of Colitis induced by Immune checkpoint blockade therapy

One of the biggest breakthroughs within oncology in the recent years has been
the development of immunotherapy: drugs that enhance the strength of immune
system to attack tumor cells. Immune cells do this naturally, however many
tumors have evolved by disabling anti-tumor immunity through cancer
immunoediting. Examples of this are anti-inflammatory cytokine production or
the upregulation of proteins that lead to T cell inactivation/exhaustion, such
as oncogenic PD-L1 (Programmed cell Death Ligand 1) expression. When PD-1
(Programmed cell Death 1) on activated T cells binds to PD-L1, the T cell will
stop proliferating and becomes exhausted. Similar anergic responses in T cells
are observed when CTLA-4 (Cytotoxic T-lymphocyte-associated 4) on T cells binds
ligands like CD80/CD86.

Over the past decades, antibodies against CTLA-4 and PD-1 or PD-L1 have been
developed aiming to unleash these breaks on exhausted T cells. Intriguingly,
this indeed leads to anti-tumor immune responses and in subgroups of patients
even to complete responses even in metastasized cancer. Given this
unprecedented potential to cure cancer, many scientists are now focusing on
finding ways to improve anti-cancer immune responses using several
immunomodulatory drugs.

Unfortunately, the use of immune checkpoint inhibitors is not completely
harmless. As can be envisioned, generalized immune activation is accompanied by
considerable immune-related adverse events (irAEs). These side effects include
ICI-associated thyroiditis, - hepatitis and colitis among others.
ICI-mediated colitis (IMC) is one of the most commonly observed irAEs which may
cause discontinuation of therapy. Often, patients with severe IMC require
hospitalization and anti-inflammatory therapies to resolve intestinal
inflammation, such as systemic prednisone, anti-TNF therapy or anti-integrin
antibodies. The interruption of the treatment and the start of
anti-inflammatory treatments that may promote tumor growth, is obviously
deleterious for the patient.

Therefore, the major challenge and largely unmet clinical need is predicting
which patients are susceptible to develop IMC. This would greatly advance the
field of immunotherapy, as patients with a high probability of IMC could be
prophylactically treated with intestinal-specific anti-inflammatory drugs to
prevent severe irAE*s and continue anti-cancer treatments.

In this proposal, we aim to unravel the factors that increase susceptibility to
IMC, including the intestinal immune composition and the microbiome
composition, in order to find predictive biomarkers for IMC susceptibility. In
parallel, we hope to find signals that keep the colonic immune response
*silent*, information that may eventually also be useful to understand immune
exhaustion in inflammatory bowel disease (IBD).

Our main objective is to determine the factors that increase susceptibility to
IMC in order to find predictive biomarkers.

Investigator initiated prospective cohort study

Burden: Patients will visit the coordinating investigator four to six times
after recruitment, depending on whether the patient develops IMC or not. During
these visits, procedures such as an IUS or sigmoidoscopy will be performed. The
goal is to schedule these assessment visits on the day of ICI-treatment or
outpatient clinic visits for standard routine care to lessen patient burden.
Venapunctures will be combined with routine testing if possible and stool
samples may be prepared at home before visiting the hospital.

Risks: A sigmoidoscopy is usually well tolerated and is performed in daily
clinical practice without use of analgesics and/or anaesthesia. Preparation for
sigmoidoscopy includes the administration of an enema prior to the
sigmoidoscopy.

Intestinal ultrasonography is a well-tolerated and non-invasive diagnostic
tool. This will be optional for all participating patients to undergo. We
expect that our study procedures will not inflict additional burden to the
subjects.

Benefit: There is no evident benefit for patients who choose to participate in
this study. It is aspired to gain new insights on the pathophysiology of IMC
and to further assess methods to predict, thus prevent the occurrence and
severity in patients undergoing ICI-treatment.