Selective Expansion and Targeting of FoxP3+CD127lo Regulatory T Cells By Low-Dose IL-2 Therapy in Active SLE

Jens Humrich¹, Caroline von Spee-Mayer², Philipp Enghard³, Angelika Rose⁴, Elise Siegert⁵, Tobias Alexander⁵, Falk Hiepe⁶, Gerd R. Burmester⁷ and Gabriela Riemekasten⁸, ¹Department of Rheumatology, University Hospital Schleswig-Holstein - Campus Lübeck, Lübeck, Germany, ²Immunology, University Hospital Freiburg, Freiburg, Germany, ³Department of Nephrology, Charité – University Medicine Berlin, Berlin, Germany, ⁴Rheumatology and Clinical Immunology, Charité – University Medicine Berlin, Berlin, Germany, ⁵Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Berlin, Germany, ⁶Rheumatology, Charité – University Medicine Berlin, Berlin, Germany, ⁷Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin, Germany, ⁸Rheumatology, University Hospital Schleswig-Holstein - Campus Lübeck, Lübeck, Germany

Meeting: ACR/ARHP Annual Meeting 2018

Keywords: clinical trials, Immunotherapy, interleukins (IL) and regulatory cells, SLE

Session Information

Date: Tuesday, October 23, 2018

Title: Systemic Lupus Erythematosus – Clinical Poster III: Treatment

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Interleukin-2 (IL-2) is crucial for the growth and survival of regulatory T cells (Treg), and thus for the control of autoimmunity. In previous studies we revealed the significance of an acquired IL-2 deficiency and related Treg defects in the pathogenesis of systemic lupus erythematosus (SLE). Here, we report the cellular responses to low-dose IL-2 therapy observed during an open-label, uncontrolled, dose escalation, phase 1/2a single-center clinical trial in patients with active SLE (EudraCT-Number: 2013-001599-40; DRKS-ID: DRKS00004858).

Methods: Twelve patients with active and refractory SLE (SLEDAI ≥ 6) were treated at our site with a low-dose IL-2 regimen consisting of four separate treatment cycles each with daily subcutaneous injections of recombinant human IL-2 (aldesleukin) at single daily doses of 0.75, 1.5 or 3.0 million IU for five consecutive days. Cells from peripheral blood were analyzed by flow cytometry at every study visit before and one day after each treatment cycle.

Results: All 12 treated patients showed highly significant cycle- and dose-dependent increases in the percentage of FoxP3+CD127lo Treg, of CD25hi cells among Treg and in the mean fluorescence intensity (MFI) of CD25 in Treg. In parallel, absolute numbers of CD25hi Treg and of FoxP3+CD127lo Treg in the peripheral blood increased significantly in a cycle-dependent fashion. By contrast, we observed only minor increases in the proportions and absolute numbers of CD25hi cells among CD3+CD4+FoxP3- conventional T cells (Tcon) and in the MFI of CD25 in Tcon. Moreover, there were no relevant changes in the absolute numbers of CD3+CD8+ T cells, of CD3+CD56+ NK T cells and of CD3-CD56+ NK cells. In addition, we noted robust and dose-dependent increases in the frequencies of Treg expressing the proliferation marker Ki67. Although significant increases in the proportions of Ki67+ Tcon were also apparent at the end of each treatment cycle, the calculated ratio between Ki67+Treg and Ki67+ Tcon continuously increased and was significantly higher at the end of the treatment phase, indicating a partial restoration of the homeostatic Treg/Tcon balance and suggesting a preferential targeting of the Treg population by low-dose IL-2 therapy.

Conclusion: Low-dose IL-2 therapy is capable to selectively expand and target the Treg population in patients with active SLE. This study also provides novel insights into the pharmacodynamics and immunological effects of low-dose IL-2 therapy.

Disclosure: J. Humrich, None; C. von Spee-Mayer, None; P. Enghard, None; A. Rose, None; E. Siegert, None; T. Alexander, None; F. Hiepe, None; G. R. Burmester, Pfizer Inc, 2,AbbVie, Eli Lilly, Gilead, Pfizer Inc, 5,AbbVie, Eli Lilly, Gilead, Pfizer Inc, 8; G. Riemekasten, None.

To cite this abstract in AMA style:

Humrich J, von Spee-Mayer C, Enghard P, Rose A, Siegert E, Alexander T, Hiepe F, Burmester GR, Riemekasten G. Selective Expansion and Targeting of FoxP3+CD127lo Regulatory T Cells By Low-Dose IL-2 Therapy in Active SLE [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/selective-expansion-and-targeting-of-foxp3cd127lo-regulatory-t-cells-by-low-dose-il-2-therapy-in-active-sle/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-expansion-and-targeting-of-foxp3cd127lo-regulatory-t-cells-by-low-dose-il-2-therapy-in-active-sle/