T-Cell Mediated Plaque Inflammation and Atherosclerosis in Stage III Melanoma Patients on (neo-)adjuvant Immune Checkpoint Inhibitors: a prospective matched cohort study

In the past decade immune checkpoint inhibitors (ICIs) have revolutionized
cancer treatment as they lead to unprecedented response rates in many types of
cancer - in particular lung cancer and melanoma - and they significantly
improved the prognosis of cancer patients. Due to the success of ICI therapy,
prescription rates have substantially increased and currently more than 40% of
all new malignancies meet the indication for a form of ICI therapy. ICIs are
very potent to combat a variety of malignancies, but their cardiovascular
toxicities are an emerging problem. Recently, studies have shown that T-cell
mediated acceleration of atherosclerosis may be an important long-term
complication of ICIs. The incidence of atherosclerotic cardiovascular adverse
events in todays* practice is currently unknown as these agents only recently
entered the clinics, but these toxicities are reported in an increasing number
of studies. Statin therapy appeared to attenuate this increase in aortic
atherosclerotic plaque.

How ICIs affect atherosclerosis in cancer patients is currently unknown. In
hyperlipidemic mice, short-term ICI treatment induced hyper-inflammatory
atherosclerotic plaque phenotype, thereby promoting atherosclerotic lesion
progression towards clinically unfavorable unstable plaques. Although limited
research has been performed on vascular inflammation after ICI therapy, several
studies found an association between the F-FDG uptake as a measure of
inflammation and cardiovascular events. The aforementioned improvement of
long-term prognosis due to ICI therapy in patients with advanced malignancies-
in conjunction and tremendous expansion of ICI therapy eligibility - thus leads
to the formation of a substantial high-risk population for atherosclerotic
cardiovascular events. There is an unmet clinical need to prospectively assess
the effects of ICIs on atherosclerosis and the subsequent atherosclerotic
cardiovascular events.

To investigate the effects of ICIs (anti-CTLA4, anti-PD1, combination
anti-CTLA4/PD1) on vascular inflammation (PET-CT) in stage III melanoma
patients. We hypothesize that the increase in vascular inflammation will be
greater in the exposure group than in the control group.

This pilot investigation - a single center prospective matched cohort study -
will enroll both patients with stage III melanoma who are scheduled to receive
(neo-)adjuvant ICI therapy and a control group of patients with stage IB/II
melanoma who receive (non-ICI) anti-cancer treatment. Patients with melanoma
stage III will be recruited from the medical oncology department of LUMC and
patients with melanoma stage IB/II will be recruited from the dermatology
department of LUMC.

Patients with melanoma stage III who are scheduled to receive ICI therapy
(exposure group) will undergo a CCTA scan in addition to routinely performed
PET-CT scans at baseline and 18 months follow-up. The control group consists of
patients with melanoma stage IB/II who will not receive ICI therapy. The
control group will undergo PET-CT scans at baseline and at 18 months follow up
The total study duration will be 3 years.

Exclusion criteria are: inability to give informed consent, severe psychiatric
disorder, history of cardiovascular disease, contra-indication for PET-CT or
(in the exposure group) CCTA scan, use of cholesterol-lowering drugs (exposure
group only), use of systemic prednisolone >10 mg/day and/or an equivalent dose
of another systemic corticosteroid, uncontrolled diabetes.

The outcome of this study will indirectly give future benefit for the treatment
of melanoma patients with ICIs, as we will gain knowledge about the process of
atherosclerosis in patients treated with ICIs, which will possibly contribute
to future prevention strategies. The blood samples are necessary to assess
cardiovascular biomarkers, but could be a small burden for the patients. By
undergoing CCTA, patients will be exposed to radiation, but, this concerns a
very minimal amount of radiation (1.3 mSv). Furthermore, we do not expect any
serious adverse outcomes related to these interventions. The results of this
study will provide insight in vascular inflammation in melanoma patients
treated with ICIs and will provide a framework for the identification of novel
therapeutics of novel therapeutic strategies to limit the cardiovascular
toxicity of ICIs, without compromising their anti-tumor efficacy. As treatment
for cancer with ICIs improves, in the future the survival-rate will probably
increase. For those patients, it is important to know the adverse effects of
ICI treatment on inflammation, in order to prevent progressive atherosclerotic
disease or even cardiac-related death. The PET-CT scans will expose the control
group to additive radiation. However, these scans and their outcomes are also
very relevant for this control patient group, as it is expected that treatment
with ICI therapy will become available for melanoma stage IIB and IIC in the
near future.