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Commenting on Meyer et al 1 our recent publication2 ‘Immunological and clinical effects of low-dose interleukin-2 (IL-2) across 11 autoimmune diseases in a single, open clinical trial’, Dr Meyer and colleagues point to the issue of concomitant background therapies that could affect the effects of low-dose IL-2. They reported a significant increase of Treg cell frequencies in peripheral blood of patients with rheumatoid arthritis treated with methotrexate, adalimumab, etanercept, golimumab and tocilizumab, which they discuss could affect the increase expected after an IL-2 treatment.
Only four rheumatoid arthritis patients were included in our study, all being treated with low-dose corticosteroids and/or low doses of immunosuppressants. Their baseline Treg evaluation was similar to that of patients with other diseases treated with similar background therapies (figure 1A). In addition, in the whole cohort of patients, we did not observe significant differences in baseline Treg values for patients receiving (1) ‘non-specific immunological therapy’ (including medications like nonsteroidal anti-inflammatory drugs for joint pain, or ursodeoxycholic acid for sclerosing cholangitis); (2) low-dose corticosteroids and/or low doses of immunosuppressants; compared with patients receiving (3) anti-tumour necrosis factor-α (TNFα) or (4) ‘combination of biological disease modifying antirheumatic drug and low doses of immunosuppressants’ (figure 1B). Furthermore, as reported in our study, there were no significant differences in the Treg response to low-dose IL-2 according to the background treatment.2
We believe that baseline levels of Tregs in peripheral blood cannot be a criteria for low-dose IL-2 treatment decision nor a robust enough biomarker of the clinical response. First, IL-2 treatment should not be limited to patients (or diseases) with qualitative or quantitative Treg deficiency as the mere presence of an autoimmune disease signals a Treg insufficiency, that is, that Tregs are unable to control the effector immune response as they should3; second, Treg peripheral blood levels may not accurately reflect Treg counts at sites where they are needed for therapeutic efficacy, that is, tissues or draining lymph nodes; third, IL-2 treatment not only expands Tregs, but also improves their fitness2 4 and reshapes their T cell receptor repertoire, both parameters likely playing a role in IL-2 therapeutic activity.
IL-2 has pleiotropic3 dose-dependent4 biological activities and patients show some heterogeneity in response to it. Future studies will have to look for biomarkers of IL-2 activity through multiple omics studies, so as to optimise precision medicine-driven modalities.
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Handling editor Josef S Smolen
Contributors MR and RL analysed data; DK drafted the reply.
Funding Funding was provided by the sponsor, the Assistance Publique - Hôpitauxde 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).
Competing interests MR, RL, 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 and DK
hold shares in ILTOO Pharma. No other potential conflicts of interest relevant to this article were reported
Provenance and peer review Commissioned; internally peer reviewed.