Low-dose use of a treatment for certain advanced cancers, aldesleukin, was well-tolerated and lessened disease activity in people with refractory systemic lupus erythematosus (SLE) taking part in a small Phase 1/2a trial.
Study results also showed patients had higher proportions of a subset of immune T-cells associated with suppression of autoimmunity. But, as its researchers and an SLE specialist added in a commentary, more testing is needed.
The study, “Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial,” appeared in the journal The Lancet Rheumatology.
Interleukin-2 (IL-2) is a signaling molecule with a key role in the survival, growth, and normal working of regulatory T-cells (Tregs), which are essential to suppressing the activation and expansion of autoreactive immune cells.
Preclinical studies suggest that IL-2 deficiency and disturbances in Tregs are implicated in SLE development, a link further supported by studies showing that short-term treatment with IL-2 reverses these cellular defects.
A team at Charité-University Medicine Berlin conducted an open-label Phase 1/2a study (DRKS00004858) to test whether low-dose aldesleukin (a recombinant version of IL-2) could safely restore Treg functioning in people with SLE. (Aldesleukin is marketed as Proleukin, by Prometheus, for patients with metastatic renal cell carcinoma or metastatic melanoma.)
The study included 12 patients (age 26–61), two of whom had already been treated with aldesleukin in 2013–14 under compassionate use. One of these patients’ case was covered in a study published in 2015. All 12 participants had moderate-to-severe disease activity despite prior use of two or more conventional therapies.
Treatment included four cycles of aldesleukin, given daily via subcutaneous (under-the-skin) injection for five days followed by a 9–16 day interval. The dose increased from 1·5 million IU in the first cycle to a maximum of 4·5 million IU depending on safety signals and on the percentage of Tregs.
Clinical and laboratory data were collected on the first day of treatment, and one day after the final injection in each cycle. Overall, the treatment period lasted nine weeks, with a subsequent nine-week follow-up period, with visits at weeks 12 and 18. Eleven patients completed the four cycles, and all 12 completed the follow-up.
The primary efficacy goal was a 100% or greater increase in the proportion of Tregs containing high levels of the CD25 protein marker at the end of treatment (day 62). Typically, SLE patients have lower proportions of these Tregs, with a decrease in their levels correlating with disease activity.
Secondary goals included reductions in disease activity – measured with the SELENA-SLEDAI tool and the BILAG score, less disease flares assessed with the SLEDAI flare index, as well as changes in levels of autoantibodies and complement proteins – a set of over 20 blood proteins forming part of the body’s immune defenses – also at day 62.
Results showed that treatment with aldesleukin was well-tolerated at lower daily doses of 0·75 to 1·5 million IU. As the frequency and severity of adverse events — fever, flu-like symptoms, headaches, and dizziness — increased in the eight patients given 3·0 million IU during the second treatment cycle, their dose was dropped back to 1·5 million.
A total of 159 adverse events were reported, almost half (47%) being treatment-related. Most treatment-related adverse events were transient and mild-to-moderate. The most frequent was injection-site reaction (20%).
No serious adverse events or infections occurred during the treatment period, the study reported. During follow-up, one of five serious adverse events — a case of peripheral ischemia — was deemed possibly related to treatment.
No clinically important changes in blood counts, liver enzymes, renal and blood clotting markers, plasma proteins, or antibodies were noted. Lung and cardiac function assessments also found no relevant changes during the study.
Eleven patients (92%) achieved the primary goal, at least doubling the percentage of CD25-positive Tregs, with significant increases being noted after each cycle and correlating with cumulative dose of aldesleukin. However, nine patients had Tregs reductions almost to baseline (study start) levels three weeks after the final treatment (at first follow-up visit).
Similar increases were noted in proliferating Tregs, and, overall, expansion of Tregs with suppressive function. The data also showed no decreases in disease-associated autoantibodies. In contrast, the levels of complement proteins C3 and C4 showed transient increases.
Ten patients (83%) experienced a reduction in disease activity at day 62, with eight showing a complete disappearance of active clinical manifestations such as arthritis and rash. All eight had lesser disease activity before the second treatment cycle. No severe disease flares were observed throughout the study.
Patients with no disease manifestations upon treatment had higher proportions of Tregs containing high CD25 amounts. The increased proportions of these cells correlated with the degree of disease activity reduction and also with the median daily dose of prednisolone.
“Low-dose IL-2 therapy can be considered as a novel targeted treatment option in SLE,” the investigators wrote. “Our results provide a valuable scientific basis for future clinical trials.”
In an accompanying comment, “Low-dose interleukin-2 for systemic lupus erythematosus?,” Daniel J Wallace, an SLE expert and associate director of the Rheumatology Fellowship Program at Cedars-Sinai, said the results “are promising but also very preliminary.”
He added that “expansion of regulatory T cells by low dose IL-2 is an exciting and challenging approach,” but one unlikely to benefit all patients, as not all people with SLE have Treg deficiency.
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