Objective Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential.
Aim We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases.
Methods We performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation.
Results ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed.
Conclusion The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.
Trial registration number NCT01988506.
- systems biology
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MR and RL contributed equally.
Handling editor Josef S Smolen
Collaborators Principal Investigator: Prof D Klatzmann MD, PhD. Methodologist: Prof E Vicaut, MD, PhD. Clinical Investigator: R Lorenzon MD. Clinical pathologist: M Rosenzwajg MD, PhD. Clinical Investigations Centers: (1) Clinical Investigation Center Paris-Est CIC-1421 Pitié-Salpêtrière Paris France: Prof C. Funck Brentano MD, PhD; J-E Salem, MD, PhD; E. Guilloux, (2)Clinical Investigation Center for Biotherapy and immunology CIC-1420 Pitié-Salpêtrière Paris France: M Barbie, N Fery, C Degbe, C Bernard, C Ribet. Clinicians and recruiting centers: (1) Prof S Aractingi MD, PhD; E Regnier, MD: Department of Dermatology, AP-HP, Cochin Hospital (2) Prof L Beaugerie MD, PhD; Prof P. Seksik: Department of Gastro-enterology, AP-HP, Saint Antoine Hospital (3) Prof F Berenbaum MD, PhD; Prof J. Sellam MD, PhD: Department of Rheumatology, APHP, Saint-Antoine Hospital (4) Prof P Cacoub MD, PhD: Department of Internal Medicine, AP-HP, Pitié-Salpêtrière Hospital (5) Prof O Chazouilleres MD, PhD, Dr C. Corpechot MD, PhD: Department of Hepatology APHP, Saint Antoine Hospital (6) Prof B Fautrel MD, PhD: Department of Rheumatology, AP-HP, Pitié-Salpêtrière Hospital (7) Dr A Mekinian, MD, PhD; Pr Fain, MD: Department of Internal Medicine, AP-HP, Saint Antoine Hospital. Treatment Management: Pharmacy, Saint Antoine Hospital, APHP, Paris, France: C Mayala PharmD; A. Daguenel Nguyen PharmD, V Quiniou Pharm D, PA Vinot Pharm D; Pharmacy, Pitié Salpêtrière Hospital APHP, Paris, France: Fanny Charbonnier-Beaupel. Regulatory affairs and Monitoring: Clinical Research and Development Department (DRCD) APHP, Paris, France: K. Seymour-Inamo; Clinical Research Unit Lariboisière, APHP, Paris, France: E. Vicaut MD, PhD; V. Jouis, A. Mekouo-Tagne, O. Tran. Data and Safety Monitoring Board: (1) Prof Jacques Eric Gottenberg: Department of Rheumatology, Hautepierre Hospital, Strasbourg (2) Prof Olivier Blétry: Department of Internal Medicine, Foch Hospital, Suresnes (3) Prof Pierre Galanaud: Department of Internal Medicine and Clinical Immunology, Antoine Béclère Hospital, Clamart.
Contributors MR participated in the design of the study, supervised immunomonitoring, analysed the results and helped write the article. RL participated in the design of the study, was the principal clinical investigator, analysed the results and helped write the article. PC participated in the design of the study and was a clinical investigator of the study. FP, KES and HPP analysed the immunological and transcriptomic results. SA, BB, LB, FB, BF, JC, OC, CC, CF, AM, ER, DS, PS, JS and J-ES were clinical investigators of the study. CR was an assistant clinical investigator and supervised the logistics. CB and AD-N were in charge of treatment management. VD and JM contributed to the study performance and regulatory affair follow-up. EV participated in the design of the study, wrote the statistical report, analysed the results and helped write the article. DK conceived and supervised the study, was the principal investigator, analysed the results and wrote the first draft of the article. All authors edited and approved the final draft of the article.
Funding Funding was provided by the sponsor, the Assistance Publique - Hôpitaux de Paris. ILTOO Pharma provided support to the sponsor for clinical trial conduct and regulatory affairs, and contributed to some statistical analyses. Additional funding came from the ANR within the Investissements d'Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom), the Recherche Hospitalo-Universitaire (ANR-16-RHUS-0001, RHU IMAP) and the European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).
Competing interests MR, RL, PC, FB, BF, PC, JS, DS, CB and DK are inventors for patent applications related to the therapeutic use of ld-IL2, which belongs to their academic institutions and has been licensed to ILTOO Pharma. MR, VD, JM and DK hold shares in ILTOO Pharma. HPP, VD and JM are employees of ILTOO Pharma. No other potential conflicts of interest relevant to this article were reported.
Patient consent Obtained.
Ethics approval The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (CPP-IdFVI) and performed in accordance with the Declaration of Helsinki and good clinical practice.
Provenance and peer review Not commissioned; externally peer reviewed.
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