Volume 144, April 2024, 103172Author links open overlay panel, , , , , , , , , , , , , , , , , , , …AbstractBackground

A Tregs insufficiency is central to autoimmune and inflammatory diseases pathophysiology and low dose interleukin-2 (IL-2LD) can specifically activate Tregs.

Objective

To assess IL-2LD therapeutic potential and select diseases for further clinical development, we performed an open-label, phase 2a, disease-finding, “basket trial” involving patients with one of 13 different autoimmune diseases.

Methods

81 patients treated with IL-2LD (1 million IU/day) for 5 days, followed by fortnightly injections. The first 48 patients received diluted Proleukin®, while the subsequent 33 received ready-to-use ILT-101®. The primary endpoint was the change in Tregs at day-8 compared to baseline. Key secondary endpoints included clinical efficacy assessments using the Clinical Global Impression (CGI) scale, disease-specific scores, and EuroQL-5D-5L.

Results

Our study unveiled a universal and significant expansion and activation of Tregs, without concomitant Teffs activation, across all 13 autoimmune diseases. Both Proleukin® and ready-to-use ILT-101® demonstrated identical effects on Tregs. CGI scores reflecting activity, severity, and efficacy were significantly reduced in the overall patient population. Disease-specific clinical scores improved in five of the six disease cohorts with at least six patients, namely ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, Sjögren's syndrome, and systemic sclerosis. Urticaria was the only severe adverse event related to treatment.

Conclusion

IL-2LD was well-tolerated, exhibiting specific Treg activation and clinical improvements across the 13 autoimmune diseases.

Clinical implication

Tregs stimulation by IL-2LD is a promising therapeutic strategy and IL-2LD holds considerable promise for integration into combinatorial therapeutic approaches.

Section snippetsTrial registration

ClinicalTrials.gov number, NCT01988506.

Methods

Most methods have previously been described in our initial report of the first 46 patients of TRANSREG. The main methods, additions and changes are described below.

Participants

Between January 2014 and February 2020, we included and treated 81 patients, among which 48 received Proleukin® and 33 received ILT-101®. Two patients were excluded from the analysis of the primary efficacy criteria because they stopped the study treatment before day 8, but were maintained in the analysis of the secondary efficacy criteria according to the protocol (Fig. 1). Twenty-two patients discontinued treatment prematurely (supplementary table SIII).

Baseline demographics and disease

Discussion

We previously reported the results of the first 46 TRANSREG patients [7]. We found that the dose and scheme of IL-2LD used was safe and selectively activates and expands Tregs without activating Teffs across the 11 AIDs of the study.

The results of the cohort expanded to 81 patients that we report here confirm i) the universal and selective effect of IL-2LD on Tregs on now 13 different diseases and ii) IL-2LD safety on a heterogeneous patient's population with different background therapies

Author contributions

RL participated in the design of the study, was principal clinical investigator, analyzed results and helped write the article; PC participated in the design of the study and was a clinical investigator of the study; FP analyzed the immunological results; CR was an assistant clinical investigator and supervised logistics; SA, BB, LB, FB, BF, CJ, CO, CC, BF, AM, ER, DS, J-E S, JS and PS, were clinical investigators of the study; EV participated in the design of the study, wrote the statistical

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 supplied the ILT-101 product. Additional funding came from a grant from the ANR within the Investissements d'Avenir.

MR, RL, PC, FB, BF, PC, JS DS and DK are inventors for patent applications related to the therapeutic use of ld-IL-2, which belongs to their academic institutions and have been licensed to ILTOO Pharma.

Ethical approval

Comité de Protection des Personnes de l'hôpital Pitié-Salpêtrière (CPP): reference number 51–13.

Agence Nationale de Sécurité des Médicaments (ANSM): reference number 130508A-32.

Acknowledgements

We thank the patients and the members of the TRANSREG-study group [7] for their participation. We thank all the personnel of the Clinical Investigation Center Paris-Est (CIC-PE), in particular C Funck-Brentano, E Guilloux, E Dasque, L Koehl and AM Chenier, and the personnel of the Clinical Investigation Center for Biotherapies (CIC–BTi), Guillaume Churlaud, Michèle Barbié, Cornélia Degbé, Natalie Féry, Anne Laure Raveu and Alexandra Roux, for their excellent help. We thank G Bensimon for his

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