Prospective Exploration of Vascular Complications Associated With the Use of Immune Checkpoint Inhibitors (ICI-Vasc)

Prospective Exploration of Vascular Complications Associated With the Use of Immune Checkpoint Inhibitors in Cancer Treatment: a Multidimensional Study of a Patient Cohort

The development of immune checkpoint inhibitors (ICIs) has revolutionized the management of many oncological diseases, and their use continues to increase. ICIs are monoclonal antibodies that target immune checkpoints such as PD-1 (programmed cell death protein 1, as seen in nivolumab, pembrolizumab, and cemiplimab), PD-L1 (programmed cell death protein 1 ligand, as seen in atezolizumab, avelumab, and durvalumab), CTLA-4 (cytotoxic T-lymphocyte antigen 4, as seen in ipilimumab and tremelimumab), or LAG-3 (lymphocyte-activating gene 3, as seen in relatlimab), which play a crucial role in immune tolerance to cancer cells.

However, the surge in ICI prescriptions has been accompanied by the occurrence of numerous side effects, some of which are severe or even fatal. ICIs have a different toxicity spectrum than conventional chemotherapy, and most toxicities result from excessive immunity against different organs.

This immune-mediated toxicity can affect various organ systems, including the heart and blood vessels. Pharmacovigilance data from clinical trials conducted by Bristol-Myers Squibb, which marketed ipilimumab (anti-CTLA-4) and nivolumab (anti-PD1), revealed 18 cases (0.09%) of myocarditis among 20,594 subjects.

While cardiac complications induced by immune checkpoint inhibitors (ICIs), particularly autoimmune myocarditis, are widely described, the impact of these treatments on the vascular system remains poorly understood. However, a variety of vascular complications have been reported, ranging from vasculitis of large, medium, and small vessels to a possible increase in arterial thrombotic events, ischemic strokes, and acute coronary syndromes.

The incidence of vasculitis appears to be between 1% and 2% of patients treated with immune checkpoint inhibitors (ICIs). This is emerging as a significant signal in various pharmacovigilance studies, suggesting the involvement of immune checkpoint derepression in the pathophysiology of vasculitis. A translational study demonstrated the major role of CTLA-4 in the pathophysiology of giant cell arteritis (GCA), although the precise mechanisms involved remain to be determined. Therefore, a specific immune environment could promote the development of vasculitis, a phenomenon reproduced by ICI administration.

The increase in arterial thrombotic vascular events was primarily observed in a matched cohort study, which showed a threefold increased risk of arterial thrombotic vascular events following the initiation of ICI therapy. These thrombotic events would coincide with the acceleration of atherosclerosis in patients treated with ICIs. This "accelerated" atherosclerosis could be linked to inflammatory changes within the plaques, causing plaque destabilization or rupture. It is also unreasonable to rule out the possibility that the accelerated atherosclerosis is related to the development of vasculitis in these patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Vascular Complications
• Intervention / Treatment: Other: Evaluation of the vascular impact of ICIs (Immune Checkpoint Inhibitors)

Detailed Description

The various mechanisms involved in vascular complications during ICI therapy could be responsible for early vascular toxicity in the aorta and its main branches, characterized by increased stiffness. This increased arterial stiffness, indicative of premature vascular aging and leading to impaired cardiocirculatory coupling, could be accompanied by subsequent cardiovascular events, or even predictive of immunological complications, even though short-term ICI use does not appear to be associated with the development of hypertension.

Thus, the extent of vascular complications induced by ICIs, the mechanisms involved, as well as the progression of vascular damage and the associated long-term consequences after treatment discontinuation in patients in remission, remain poorly understood. In particular, the hypothesis of this research is that an increase in arterial stiffness is induced very rapidly by ICIs due to immune modifications and that the persistence of this increase in stiffness after stopping treatment is associated with an increased cardiovascular risk in patients.

Given the increasing use of immune checkpoint inhibitors (ICIs) and the number of patients treated, a better understanding of the vascular impact of these drugs is both necessary and urgent.

The results obtained should allow us to determine, for the first time, the vascular impact of ICIs, as well as to identify the immunological mechanisms involved and the long-term prognosis consequences for patients due to potential premature arterial aging induced by ICI treatment. This is a multidisciplinary clinical-biological research study involving the Clinical Pharmacology Department for vascular investigations, the Clinical Investigation Center (CIC-CRB 1404) for biological sampling, and the Dermatology Department (Dr. Janela) for volunteer recruitment and follow-up.

This cohort study will also be combined with pharmacoepidemiological and pharmacovigilance studies using the French National and International Pharmacovigilance Databases (BNPV and VigiBase) (Dr. Nathalie Massy). On the other hand, experimental studies will be conducted in murine models of vascular pathologies within the UMR Inserm 1096 EnVI (Dr. Antoine Hérault's PhD thesis, supervised by Professor Fabienne Tamion, Dr. Dominique Modovar and Dr. Ebba Brakenhielm) in order to better understand the role of ICIs in vascular pathophysiology and ultimately be able to propose care and/or treatments adapted to patients receiving ICIs in order to prevent or limit their adverse effects including deleterious cardiovascular consequences.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: vincent VF FERRANTI, ARC; Phone Number: +33 02 32 88 82 65; Email: Vincent.Ferranti@chu-rouen.fr
• Study Contact Backup: Name: Nabila NL LAAJAIL, Director; Phone Number: +33 02 32 88 82 65; Email: Nabila.Laajail@chu-rouen.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

patients treated with an Immune Checkpoint Inhibitor (ICI) as monotherapy (curative or as an adjunct to surgery) or a combination of ICIs in the dermatology oncology department

Description

Inclusion Criteria:

• Patient treated with an ICI (nivolumab, pembrolizumab, atezolizumab, ipilimumab, cemiplima, or any novel antibody directed against PD-1, PD-L1, CTLA-4, or LAG-3) as monotherapy or in combination with another ICI or with radiotherapy,
• Patient over 18 years of age,
• WHO performance status: 0 to 2,
• Oral informed consent,
• Patient affiliated with or beneficiary of a social security scheme.

Exclusion Criteria:

• History of ICI treatment,
• History of chemotherapy or targeted therapy within the last 4 weeks,
• Stage 4 PAD,
• Severe Raynaud's syndrome,
• Removal of both hands and/or both feet,
• Removal of the right hand/left foot or the left hand/right foot,
• Patient deprived of liberty by an administrative or judicial decision or patient under legal protection, guardianship, or curatorship,
• Pregnant or breastfeeding woman,
• Patient unable to understand the study for any reason or to comply with the trial requirements (language barrier, psychological, geographical, etc.).

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine if there is an increase in aortic arterial stiffness 6 to 8 weeks after the start of ICI treatment.	Evaluation of the variation in pulse wave velocity (PWV) measured by photoplethysmography (Popmeter®, Axelife) between the initial value and the value after 6 to 8 weeks of ICI treatment.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine if there is an increase in aortic arterial stiffness one year after the start of ICI treatment	Evaluation of the change in PVO measured by photoplethysmography (Popmeter®, Axelife) between the initial value and the value after 1 year of ICI treatment	1 year
Determine if there are, 6 to 8 weeks after the start of ICI treatment: An alteration in systemic hemodynamics and cardiocirculatory coupling,	Evaluation of brachial arterial pressures by photoplethysmography (Popmeter)	8 weeks
Determine if there are one year after the start of ICI treatment: An alteration in systemic hemodynamics and cardiocirculatory coupling,	Evaluation of brachial arterial pressures by photoplethysmography (Popmeter)	1 year
Determine if there are, 6 to 8 weeks after the start of ICI treatment: An alteration in systemic hemodynamics and cardiocirculatory coupling,	Evaluation of aortic pressures by photoplethysmography (Popmeter)	8 weeks
Determine if there are, 6 to 8 weeks after the start of ICI treatment: An alteration in systemic hemodynamics and cardiocirculatory coupling,	Evaluation of aortic augmentation index by photoplethysmography (Popmeter)	8 weeks
Determine if there are one year after the start of ICI treatment: An alteration in systemic hemodynamics and cardiocirculatory coupling,	Evaluation of aortic pressures by photoplethysmography (Popmeter)	1 year
Determine if there are one year after the start of ICI treatment: An alteration in systemic hemodynamics and cardiocirculatory coupling,	Evaluation of aortic augmentation index by photoplethysmography (Popmeter)	1 year
Llink between overall and progression-free survival and ICI treatment at 1 year, 2 years and 3 years.	Determine if there is a link between overall and progression-free survival and ICI treatment at 1 year	1 year
Llink between overall and progression-free survival and ICI treatment at 1 year, 2 years and 3 years.	Determine if there is a link between overall and progression-free survival and ICI treatment at 2 years	2 years
Llink between overall and progression-free survival and ICI treatment at 1 year, 2 years and 3 years.	Determine if there is a link between overall and progression-free survival and ICI treatment at 3 years.	3 years
Link between the occurrence of cardiac and vascular complications and treatment with ICI	Determine if there is a link between the occurrence of cardiac and vascular complications and treatment with ICI at 6-8 weeks	8 weeks
Link between the occurrence of cardiac and vascular complications and treatment with ICI	Determine if there is a link between the occurrence of cardiac and vascular complications and treatment with ICI at 1 year	1 year
Link between the occurrence of cardiac and vascular complications and treatment with ICI	Determine if there is a link between the occurrence of cardiac and vascular complications and treatment with ICI at 2 years	2 years
Link between the occurrence of cardiac and vascular complications and treatment with ICI	Determine if there is a link between the occurrence of cardiac and vascular complications and treatment with ICI at 3 years.	3 years
Increase in pro- or anti-inflammatory plasma cytokines (IL-1)	Measurement of plasma concentrations of pro- or anti-inflammatory cytokines (IL-1)	8 weeks
Increase in pro- or anti-inflammatory plasma cytokines (IL-6)	Measurement of plasma concentrations of pro- or anti-inflammatory cytokines (IL-6)	8 weeks
Increase in pro- or anti-inflammatory plasma cytokines (IL-10)	Measurement of plasma concentrations of pro- or anti-inflammatory cytokines (IL-10)	8 weeks
Increase in pro- or anti-inflammatory plasma cytokines (IL-17)	Measurement of plasma concentrations of pro- or anti-inflammatory cytokines (IL-17)	8 weeks
Increase in pro- or anti-inflammatory plasma cytokines ( TNF-α)	Measurement of plasma concentrations of pro- or anti-inflammatory cytokines (TNF-α)	8 weeks
Increase in pro- or anti-inflammatory plasma cytokines (IFN-γ)	Measurement of plasma concentrations of pro- or anti-inflammatory cytokines (IFN-γ)	8 weeks
Modification of the level of lymphocyte and monocyte activation (CD3)	Determination of the expression of lymphocyte and monocyte markers (CD3)	8 weeks
Modification of the level of lymphocyte and monocyte activation (CD4)	Determination of the expression of lymphocyte and monocyte markers (CD4)	8 weeks
Modification of the level of lymphocyte and monocyte activation (CD8)	Determination of the expression of lymphocyte and monocyte markers (CD8)	8 weeks
Modification of the level of lymphocyte and monocyte activation (CD44)	Determination of the expression of lymphocyte and monocyte markers (CD44)	8 weeks
Modification of the level of lymphocyte and monocyte activation (CD62L)	Determination of the expression of lymphocyte and monocyte markers (CD62L)	8 weeks
Modification of the level of lymphocyte and monocyte activation (HLA-DR)	Determination of the expression of lymphocyte and monocyte markers (HLA-DR)	8 weeks
Modification of the level of lymphocyte and monocyte activation (CD69)	Determination of the expression of lymphocyte and monocyte markers (CD69)	8 weeks
Modification of the level of lymphocyte and monocyte activation (CD14)	Determination of the expression of lymphocyte and monocyte markers (CD14)	8 weeks
Modification of the level of lymphocyte and monocyte activation (CD16)	Determination of the expression of lymphocyte and monocyte markers (CD16)	8 weeks

Collaborators and Investigators

• Sponsor: University Hospital, Rouen
• Investigators: Principal Investigator: Jérémy JB BELLIEN, Professor, Univerity Rouen Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): June 1, 2031

Study Registration Dates

• First Submitted: April 10, 2026
• First Submitted That Met QC Criteria: April 10, 2026
• First Posted (Actual): April 17, 2026

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: immune checkpoint inhibitors; cancer therapy
• Additional Relevant MeSH Terms: Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Immune Checkpoint Inhibitors
• Other Study ID Numbers: 2025/0494/OB; 2026-A00192-49 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No