BACKGROUND

Atherosclerosis is a chronic inflammatory disease of the artery wall. Regulatory T cells (Tregs) limit inflammation and promote tissue healing. Low doses of interleukin (IL)-2 have the potential to increase Tregs, but its use is contraindicated in patients with ischemic heart disease.

METHODS

In this randomized, double-blind, placebo-controlled, dose-escalation trial, we tested lowdose subcutaneous aldesleukin (recombinant IL-2), given once daily for five consecutive days. In Part A, the primary endpoint was safety, and patients with stable ischemic heart disease were randomized to placebo or to one of 5 dose groups (range 0.3-3.0 x10 6 IU/day). In Part B, patients with acute non-ST elevation myocardial infarction or unstable angina were randomized to placebo or to one of 2 dose groups (1.5 and 2.5 x10 6 IU/day). The coprimary endpoints were safety and the dose required to increase circulating Tregs by 75%. Single-cell RNA-sequencing of circulating immune cells was used to provide mechanistic assessment of the effects of aldesleukin.

RESULTS

Forty-four patients were randomized in the study, 26 patients in Part A and 18 patients in Part B. In total, 3 patients withdrew prior to dosing; 27 received active treatment, and 14 received placebo. The majority of adverse events were mild. Two serious adverse events occurred, with one occurring after drug administration. In Parts A and B, there was a dosedependent increase in Tregs. In Part B, the estimated dose to achieve a 75% increase in Tregs was 1.46 x10 6 IU (95%CI 1.06 – 1.87). Single-cell RNA-sequencing demonstrated the engagement of distinct pathways and cell-cell interactions.

CONCLUSION

In this phase 1b/2a study, low-dose IL-2 expanded Tregs without adverse events of major concern. Larger trials are needed to confirm safety and to further evaluate efficacy of lowdose IL-2 as an anti-inflammatory therapy in patients with ischemic heart disease. (Funded by the Medical Research Council and the British Heart Foundation; ClinicalTrials.gov number, NCT03113773)