Therapeutic evaluation of low‐dose IL‐2‐based immunomodulatory approach in patients with early AD

Abstract Background Chronic innate neuroinflammation mediated by microglia and astrocytes in response to Aβ and pathological Tau species is a cardinal feature of AD that contributes to disease pathogenesis. Accumulating evidence now also highlight an instrumental role of T cells and peripheral‐central immune crosstalk in the pathophysiology of AD. Both preclinical and clinical reports suggest the potential therapeutic interest of peripheral immunomodulatory approaches aimed at amplifying regulatory T cells (Tregs), e.g. through low‐dose IL‐2 treatment, as a strategy for rebalancing T cell subsets and proper central innate neuroinflammation towards beneficial neuroinflammatory patterns. Method Our study aims at evaluating the therapeutic efficacy and safety of low‐dose IL‐2 immunomodulatory treatment in 35 patients with early AD, in a randomized (2:1), double blind, placebo‐controlled phase II clinical trial. Treatment consists in 21 cures of subcutaneous injections of either placebo or low‐dose of IL‐2 (PROLEUKIN®) at 1 MIU/day for 5 consecutive days for the first week (induction phase), then one injection per week for 16 weeks from day 15 (maintenance phase; total duration of treatment: 18 weeks). Patients are followed‐up for cognitive and functional assessment at 6, 12 and 18 months after the first injection. All subjects undergo [ 18 F]‐DPA‐714‐PET/MRI at inclusion and 18 months after treatment induction, for monitoring the evolution of brain neuroinflammation. Result An intermediate analysis of the variation of Tregs percentage was performed after 9 patients were included and treated for 4 doses into the maintenance phase. Percentages of Tregs, among both CD4+ or total CD3+ T cells, showed a 1.5‐fold increase in the treated group (n = 6), while remaining stable in the placebo group (n = 3), as expected. One patient decided to discontinue the treatment because of depression, which appears unlikely to be treatment‐related. No other adverse effect was observed. Conclusion Our intermediate biological analysis evidence a 1.5‐fold increase in Tregs percentages after 4 doses of the maintenance phase, without any significant adverse effect. These data validate our predefined objective of Treg amplification and thus target engagement, while supporting optimal safety of the treatment.