Induction of regulatory T cells and efficacy of low-dose interleukin-2 in systemic sclerosis: interventional open-label phase 1-phase 2a study

Abstract

Background: Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2_LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc.

Objective: We aimed to assess the safety and biological efficacy of IL-2_LD in patients with SSc.

Methods: As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6.

Results: At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4⁺ T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2_LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period.

Conclusion: IL-2_LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2_LD therapeutic efficacy in SSc.

Keywords: Autoimmune Diseases; Scleroderma, Systemic; T-Lymphocyte subsets.

Figure 1

Treg lymphocytes (%) among CD4+T lymphocytes changes during TRANSREG trial data represent fold changes in Tregs (A) as percentages among CD4+T cells in mean from day 1 to month 6; (B) as cells/mm3 in mean from day 1 to month 6; (C) as ratio Tregs/Teff in mean from day 1 to month 6. Statistics were made on raw data (*p<0.05, **p<0.01, ***p<0.001).