Low dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndrome (LILACS)

Background Regulatory T lymphocytes (Tregs) are critical for immune homeostasis. Pre-clinical models have demonstrated that Tregs can modulate post-ischaemic immune responses and promote myocardial healing. Patients with ischaemic heart disease (IHD) display reduced anti-inflammatory Tregs and increased pro-inflammatory effector T cells (Teffs). Low-dose interleukin-2 (ld-IL2) has been shown to increase Tregs in patients with autoimmune diseases but is currently contraindicated in patients with IHD. Purpose To assess the safety and pharmacodynamic effect of ld-IL-2 in patients with IHD. Methods LILACS was a prospective, randomised, double-blind, placebo-controlled, dose-escalation, Phase I/II clinical trial, which tested ld-IL-2 (aldesleukin) given once daily subcutaneously, for five consecutive days. In Part A, 25 patients with stable IHD were randomised (drug:placebo ratio of 3:2) in 5 dose groups (0.3, 0.6, 1.2, 2.4 and 3x106 IU/day); whilst in Part B, 16 patients with non-ST elevation myocardial infarction (NSTEMI) were randomised (drug:placebo ratio of 6:2) in two dose groups (1.5 and 2.5x106 IU/day). Follow up was performed the day after dosing and again 7 days later. Doses were determined after blinded review. An independent committee reviewed unblinded data prior to commencing Part B. The primary endpoint was safety in parts A and B. Additionally in Part B, a co-primary endpoint was to calculate the dose required to increase Tregs by 75%. [NCT03113773] Results Ld-IL2 was well tolerated for all dose groups with the commonest adverse events being mild injection site reactions. Two serious adverse events, not considered to be drug related, occurred in Part B – one prior to dosing and resulting in withdrawal. The other was a recurrent NSTEMI after dosing ended in a patient with severe triple vessel coronary artery disease awaiting urgent bypass surgery. In Part A, Tregs increased with dose escalation whilst no Teff increases were noted (Figure 1A). In Part B, patients treated with 1.5 and 2.5x106 IU/day doses had a median increase in Tregs of 80.5% (CI 36.2–124.7%, p=0.003) and 108.3% (CI 55.3–161.3%, p=0.002) respectively (Figure 1B). A linear regression model estimated an increase of 43.3% (CI 23.6–63.0%, p=0.0003) per unit dose. The estimated dose to achieve a 75% increase in Tregs was 1.46x106 IU/day (CI 1.06–1.87). No increase in Teffs cells were seen however, a dose-dependent decrease was measured in B cells, whilst NK cells and eosinophils increased at the top 2.5 and 3x106 IU/day dose. A panel of 29 cytokines and chemokines showed a dose-dependent type 1 and 2 cytokine response. Single-cell RNA sequencing was performed on immune cells before and after dosing. Conclusions Ld-IL2 was safe and well-tolerated. An induction dose of 1.5x106 IU per day for 5 days provided an effective expansion of Tregs without increasing Teffs. This work provides important data for the future therapeutic use of ld-IL-2 which is ongoing. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Medical Research Council, British Heart Foundation Cambridge Centre of Excellence