Prospective Exploration of Vascular Complications Associated With the Use of Immune Checkpoint Inhibitors

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.

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.

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.).