medwireNews: The low-dose recombinant human interleukin (IL)-2 therapy aldesleukin has a favorable safety profile and may restore regulatory T-cell homeostasis in people with systemic lupus erythematosus (SLE), suggest findings from a proof-of-concept phase I/IIa clinical trial.
Jens Humrich (University Hospital Schleswig, Lübeck, Germany) and co-investigators explain that “there is strong evidence from preclinical studies that shortage of IL-2 and related disturbances in homoeostasis of regulatory T cells have an important role in the pathogenesis of SLE,” leading them to hypothesize that low-dose IL-2 therapy could have therapeutic potential.
The single-center PRO-IMMUN trial included 12 patients with SLE and moderate-to-severe disease activity despite prior treatment with two or more conventional therapies who were treated with four cycles of daily subcutaneous aldesleukin for 5 consecutive days, with a washout period of 9 days between the first two cycles, and of 16 days between the remaining cycles.
Aldesleukin was given at a dose of 1.5 million international units (IU) in the first cycle, with subsequent increases to 3.0 followed by 4.5 million IU if prespecified safety events did not occur and the proportion of regulatory T cells was no higher than 50% of CD3+ CD4+ T cells. Dose reductions to a minimum of 0.75 million IU were also permitted.
Humrich et al report in The Lancet Rheumatology that aldesleukin was “well tolerated” at maximum daily doses of 1.5 million IU/day, but the eight participants who received the 3.0 million IU daily dose experienced an increased frequency of adverse events (AEs) including fever and chills (n=4), arthralgia and myalgia (n=4), influenza-like symptoms, headache, and dizziness (n=1 for each), resulting in dose reduction to 1.5 million IU/day.
In all, 47% of 159 AEs that occurred over the study period were considered to be treatment-related. The investigators note that the majority of AEs were mild-to-moderate in severity and resolved during the washout periods.
“Considering the dose-dependent side-effects of low-dose IL-2 therapy recorded in our study, we propose that the dose of IL-2 should be limited to a maximum of 7.5 million IU per 5-day cycle or 1.5 million IU per day,” they say.
The investigators found that 92% of patients achieved the primary efficacy endpoint, defined as a 100% or greater increase in the proportion of T cells expressing high levels of CD25 among circulating CD3+ CD4+ FOXP3+ CD127lo regulatory T cells after four cycles of treatment (day 62).
Moreover, median SELENA-SLEDAI score decreased from 10.0 points at baseline to 5.0 points at day 62, and 67% of participants achieved a clinical response according to the disappearance of at least one clinical manifestation of SELENA-SLEDAI.
These findings provide “preliminary evidence for the potential of low-dose IL-2 therapy to decrease disease activity in patients with refractory SLE,” and “a valuable scientific basis for future clinical trials,” write Humrich and team.
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