Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial

Regulatory T (T_reg) cells are powerful endogenous modulators of the immune response and their levels are reduced in patients with acute coronary syndromes (ACSs). Low-dose interleukin-2 (IL-2) has been shown to increase T_reg cell levels, potentially providing an immunomodulatory strategy in ACSs. The IVORY trial was a double-blind, placebo-controlled, phase 2 trial in which patients presenting with ACSs and high-sensitivity C-reactive protein levels >2 mg l^-1 were randomized in a 1:1 ratio to receive subcutaneous low-dose IL-2 (1.5 × 10⁶ IU) or placebo for 8 weeks. [¹⁸F]Fluorodeoxyglucose positron emission tomography-computed tomography of the ascending aorta and carotid arteries was performed before and after treatment. Here the primary outcome was the difference in arterial inflammation in the index vessel (the vessel with the highest average maximum target-to-background ratio pre-treatment) on follow-up imaging between the two groups (placebo = 29 (female-to-male ratio (F-to-M) = 6:23); low-dose IL-2 = 31 (F-to-M = 3:28)). At the end of treatment, arterial inflammation was -0.171 (-7.7%) lower in the low-dose IL-2 group compared to the placebo group (95% confidence interval -0.308 to -0.034, P = 0.015). In secondary efficacy analyses, the difference in arterial inflammation between the low-dose IL-2 and placebo groups was greater (-8.3%, P = 0.009) in more inflamed segments and low-dose IL-2 treatment increased T_reg cell levels compared to placebo (P < 0.0001). Low-dose IL-2 treatment appeared to be safe, with no major adverse cardiovascular events at the 2-year follow-up, compared to three patients with such events in the placebo group. In conclusion, in patients with ACSs, low-dose IL-2 safely increases T_reg cell levels and reduces arterial inflammation. The clinical benefit of low-dose IL-2 requires validation in larger studies. ClinicalTrials.gov registration: NCT04241601 .