Immune checkpoint inhibition associated cardiovascular adverse events in cancer patients

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and are
available for different types of cancer. However, several studies reported the
increased risk of arterial thromboembolism such as mycardial infarction and
stroke. In these studies, patients on ICI treatment have a 4-5 fold increased
risk of an ischemic event compared to cancer patients on other therapies.
Pre-clinical date suggest that accelerated atherosclerosis with infiltration of
immune cells is an important factor, although the mechanism is still unknown.

Primary objective: To assess the effect of ICI on progression of coronary
non-calcified plaque volume and ICI-related cardiovascular events by measuring
differences in plaque burden using repeated CCTA.
Secondary objectives:
- To evaluate the relation between the duration and intensity of ICI therapy
and progression of coronary and carotid non-calcified plaque volume;
- To evaluate clinical predictors and plasma and fecal biomarkers for
progression of non-calcified plaque volume during ICI treatment;
- To evaluate the association between ICI therapy and arterial and venous
thromboembolic events.

This is a single-center, observational, prospective, parallel-group study of
patients with different solid tumor types. Patients over 50 years with a solid
tumor will be enrolled prior to start of therapy. At baseline, prior to start
treatment, CCTA and CTA carotid are performed to determine the baseline
coronary an carotid artery plaque burden, if present. After 12 months of
treatment, CT scans are repeated to assess the difference in progression of
plaque burden. At baseline and at days 90 (±7), and 365 (±21), blood will be
drawn for circulating immune cells, cytokines, cardiovascular risk profile
(i.g. lipid profile), markers of endothelial cell activation, and coagulation.
Clinical data will be collected at every visit and include medication use,
physical examination and vital signs. Feces will be collected for shotgun
microbiota analysis at baseline and 12 months post-ICI. Clinical outcome on the
incidence of ATE, VTE, immune-related adverse events, tumor response and death
of any cause will be collected every visit (at baseline, day 90 and 12 months
at end of treatment and annualy for 5 years after start of treatment. To study
the potential causal effects of ICI therapy, we will compare cancer patients
eligible for ICI therapy vs patients on other treatment regimes.

Blood withdrawal for clinical laboratory assessment will include 150 mL (3 time
points). Venapunction and intravenous cannulation will result in minor
discomfort, with a small chance of hematoma occurrence. The CTA will
approximately have a duration of 10 minutes. Radiation exposure will be 9.6 mSv
in two years, slightly elevated compared to background radiation in the
Netherlands (~2.9 mSv/year). If possible, we will combine CTA imaging with
regular clinical care follow-up scans. Another potential risk is the use of
iodinated contrast, which can induce contrast nephropathy. However, this risk
is very low with low-dose, low-osmolality contrast media, and probably still
overestimated in current practice. Risk factors for developing contrast
nephropathy mainly include pre-existent renal insufficiency, which is one of
our exclusion criteria. In addition to the low occurrence of contrast
nephropathy, when occurring in patients without pre-existent renal
insufficiency, this is mostly a reversible temporary decline in eGFR.