{"doi":"10.1053/j.gastro.2023.03.230","title":"Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis","abstract":"Ulcerative colitis (UC) represents an inflammatory condition of the human colon believed in part to be mediated by dysregulation of the host immune system including potentially inadequate mucosal regulatory T-cell (Treg) responses.1Chang J.T. N Engl J Med. 2020; 383: 2652-2664Crossref PubMed Scopus (445) Google Scholar,2Laukova M. Glatman Zaretsky A. Eur J Immunol. 2023; 53e2250007Crossref PubMed Scopus (8) Google Scholar Low-dose (LD) interleukin 2 (IL2) has been shown to expand peripheral Tregs and ameliorate various inflammatory diseases in mouse models3Humrich J.Y. et al.Proc Natl Acad Sci U S A. 2010; 107: 204-209Crossref PubMed Scopus (139) Google Scholar, 4Grinberg-Bleyer Y. et al.J Exp Med. 2010; 207: 1871-1878Crossref PubMed Scopus (336) Google Scholar, 5Hulme M.A. et al.Diabetes. 2012; 61: 14-22Crossref PubMed Scopus (106) Google Scholar, 6Bonnet B. et al.J Immunol. 2016; 197: 188-198Crossref PubMed Scopus (42) Google Scholar as well as in human trials.7Saadoun D. et al.N Engl J Med. 2011; 365: 2067-2077Crossref PubMed Scopus (620) Google Scholar, 8Koreth J. et al.N Engl J Med. 2011; 365: 2055-2066Crossref PubMed Scopus (887) Google Scholar, 9Rosenzwajg M. et al.Ann Rheum Dis. 2019; 78: 209-217Crossref PubMed Scopus (258) Google Scholar Additionally, we have previously reported amelioration of colitis in humanized mice after LD IL2 treatment.10Goettel J.A. et al.Cell Mol Gastroenterol Hepatol. 2019; 8: 193-195Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar We hypothesize that LD IL2-mediated expansion of Tregs may suppress disease in UC and provide a novel treatment approach. Here, we assess whether LD IL2 is safe in UC patients, expands Tregs, and affects underlying immune mechanisms. We conducted an open-label phase 1b/2a 8-week induction trial of daily subcutaneous LD IL2 (Proleukin, Prometheus) in patients with moderate to severe UC. A total of 26 adult patients with active disease (total Mayo score, 6–10) and failure of response to ≥1 UC therapy were enrolled (Supplementary Table 1). The primary objectives were assessment of safety and tolerability of LD IL2 and determination of the maximum tolerated dose (MTD) via a 3 + 3 design with 3 dose-escalation cohorts: 0.3 × 106 IU/m2/d (dose A), 1 × 106 IU/m2/d (dose B) (MTD in Graft vs Host Disease [GvHD]8Koreth J. et al.N Engl J Med. 2011; 365: 2055-2066Crossref PubMed Scopus (887) Google Scholar), or 1.5 × 106 IU/m2/d (dose C) with an additional 10 enrolled at the MTD, once determined. Secondary outcomes included determination of efficacy as measured by clinical response (decrease in total Mayo score of ≥3 or ≥30% at week 8) and clinical remission (a total Mayo score of ≤2, with no individual subscore exceeding 1, including the week 8 Mayo endoscopic score). Flexible sigmoidoscopy was performed before treatment and at week 8. Laboratory and clinical parameters were assessed every 1 to 2 weeks. Flow cytometry was performed on peripheral blood mucosal samples to assess changes in Treg and conventional T-cell (Tcon) populations as well as activation states. Overall, LD IL2 was well tolerated, with common (occurring in >10% of patients) mild adverse events including injection site reactions, fever, and malaise across all doses. There were no serious adverse events and no deaths. One protocol-defined dose-limiting toxicity (DLT) was observed, a maculopapular rash at the injection site of a dose B patient, who was withdrawn from the study. Six additional patients withdrew because of exacerbation of UC (n = 2), uveitis (n = 1), and low-grade systemic symptoms (n = 2). Ultimately, 4 participants received dose A, 7 received dose B, and 5 received dose C. Although no dose C participants experienced a DLT, none experienced a clinical response, and all reported malaise. Therefore, although dose C qualified as the MTD, dose B was deemed the maximum efficacious dose (MED), and after discussion with the study data safety monitoring board, and an additional 10 pa","journal":"Gastroenterology","year":2023,"id":323928,"datarank":1.06747864812426,"base_score":3.58351893845611,"endowment":3.58351893845611,"self_citation_contribution":0.5375278407684165,"citation_network_contribution":0.5299508073558433,"self_endowment_contribution":0.5375278407684165,"citer_contribution":0.5299508073558433,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":35,"citers_with_citation_signal":25,"citers_with_endowment":25,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":5781,"name":"Vanessa Mitsialis","orcid":"0000-0002-1186-3616","position":1,"is_corresponding":false},{"id":1039310,"name":"James B. 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