Low-dose interleukin-2 therapy in active systemic lupus erythematosus (LUPIL-2): a multicentre, double-blind, randomised and placebo-controlled phase II trial

Abstract

ObjectivesA regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase II proof-of-concept trial to evaluate the efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard treatment.MethodsWe randomly assigned 100 patients in a 1:1 ratio to receive either 1.5 million IU/day of subcutaneous IL-2 (ILT-101) or placebo for 5 days followed by weekly injections for 12 weeks. Clinical efficacy was assessed at week 12 in a predefined hierarchical analysis of (1) the SLE responder index-4 (SRI-4) response as a primary end point, and of (2) relative and (3) absolute changes in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index scores as key secondary end points.ResultsThe primary end point was not met in the intention-to-treat population (ILT-101: 68%, placebo: 58%; p=0.3439), due to a 100% SRI-4 response rate in the placebo group from the two sites from Bulgaria. A post hoc per-protocol analysis on a prespecified population that excluded patients from these two sites (n=53) showed a statistically significant difference for the SRI-4 response rate (ILT-101: 83.3%; placebo: 51.7%; p=0.0168), and for the two key secondary end points, accompanied by differences in several secondary exploratory end points. ILT-101 was well tolerated and there was no generation of antidrug antibodies.ConclusionsThe post hoc hierarchical analysis of the primary and key secondary end points in a per-protocol population, complemented by the exploratory analyses of multiple other secondary end points, support that low-dose IL-2 is beneficial in active SLE.Trial registration numberNCT02955615.

Dysregulation and chronicity of pathogenic T cell responses in the pre-diseased stage of lupus

“…Indeed, it was shown in murine and later also in human SLE that an acquired and progressive deficiency of the cytokine interleukin-2 (IL-2), an essential growth and survival factor for Treg, promotes an imbalance between Treg and effector/memory CD4 + T cells, which was associated with accelerated disease activity ( 16 – 18 ). These pathophysiological findings have stimulated the successful translation of low-dose IL-2 therapy into clinical trials aiming to restore Treg activity in patients with active SLE ( 19 – 24 ).…”

Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes

“…The use of much lower doses of interleukin-2 (IL-2) than employed in cancer therapy has shown clinical efficacy in a number of inflammatory and autoimmune conditions, by stimulating a subset of CD4 + T cells expressing high levels of the high-affinity trimeric IL-2 receptor, designated as regulatory T (Treg) cells [1][2][3][4][5][6][7][8][9][10][11] . In the autoimmune disease type 1 diabetes (T1D), the genetic association with the IL-2 pathway in mice 12 and in humans 13,14 , combined with preclinical studies 15,16 , have provided a strong rationale for the development of low-dose (LD)-IL-2 immunotherapy.…”

CD4+T cell subset imbalances in rheumatoid arthritis

“…Our study shows large heterogeneity across patients with some with a predominantly Th1 profile, others a Th17 profile, or a Th1-like Th17 profile, while others are mainly characterised by a low IL-2 + Treg profile. As an example, stratifying patients by their IL-2 + Treg titres may dictate response to low-dose IL-2 therapy, as has now been successfully trialled in lupus [42] and RA [43]. Furthermore, a Japanese group found that stratified medicine for psoriatic arthritis patients increased response rates significantly [16].…”