Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis

• DOI: 10.1053/j.gastro.2023.03.230
• Publication Date: 2023-04-07T00:50:02Z
• Authors: Jessica R. Allegr...; Vanessa Mitsialis; James B. Canavan; Scott B. Snapper; Matthew Hamilton; Jared Barends; Madeline Carrellas; Katherine Freer; Jordan Gringauz; Julia Green; Noah Herwood; Jonathan Hurtado; Ryan Kelly; Jennifer Mitri; Caroline Rourke; Gwen Saccocia; Sydney Whitcomb; Enju Liu; David Klatzmann; Punyanganie de Silva; Frank A. Farraye; Joseph D. Feuerstein; Alan Moss; Samir A. Shah; Joshua R. Korzenik; Athos Bousvaros; John Koreth; Robert Soiffer; Jerome Ritz; Tanya Logvinenko; Ashwin Ananthakri...; Hans Herfath
• Keywords: Web of science

Ulcerative colitis (UC) represents an inflammatory condition of the human colon believed in part to be mediated by dysregulation 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 Immunol. 2023; 53e2250007Crossref (8) Scholar Low-dose (LD) interleukin 2 (IL2) has been shown expand peripheral Tregs and ameliorate various diseases mouse models3Humrich J.Y. et al.Proc Natl Acad Sci U S 2010; 107: 204-209Crossref (139) Scholar, 4Grinberg-Bleyer Y. al.J Exp 207: 1871-1878Crossref (336) 5Hulme M.A. al.Diabetes. 2012; 61: 14-22Crossref (106) 6Bonnet B. 2016; 197: 188-198Crossref (42) as well trials.7Saadoun D. al.N 2011; 365: 2067-2077Crossref (620) 8Koreth J. 2055-2066Crossref (887) 9Rosenzwajg al.Ann Rheum Dis. 2019; 78: 209-217Crossref (258) Additionally, we have previously reported amelioration humanized mice after LD IL2 treatment.10Goettel J.A. al.Cell Mol Gastroenterol Hepatol. 8: 193-195Abstract Full Text PDF (25) We hypothesize that IL2-mediated expansion may suppress disease UC provide a novel treatment approach. Here, assess whether is safe patients, expands Tregs, affects underlying mechanisms. conducted open-label phase 1b/2a 8-week induction trial daily subcutaneous (Proleukin, Prometheus) patients with moderate severe UC. A total 26 adult active (total Mayo score, 6–10) failure response ≥1 therapy were enrolled (Supplementary Table 1). The primary objectives assessment safety tolerability determination maximum tolerated dose (MTD) via 3 + design dose-escalation cohorts: 0.3 × 106 IU/m2/d (dose A), 1 B) (MTD Graft vs Host Disease [GvHD]8Koreth Scholar), or 1.5 C) additional 10 at MTD, once determined. Secondary outcomes included efficacy measured clinical (decrease score ≥3 ≥30% week 8) remission (a ≤2, no individual subscore exceeding 1, 8 endoscopic score). Flexible sigmoidoscopy was performed before 8. Laboratory parameters assessed every weeks. Flow cytometry on blood samples changes Treg conventional (Tcon) populations activation states. Overall, tolerated, common (occurring >10% patients) mild adverse events injection site reactions, fever, malaise across all doses. There serious deaths. One protocol-defined dose-limiting toxicity (DLT) observed, maculopapular rash B patient, who withdrawn from study. Six withdrew because exacerbation (n = 2), uveitis 1), low-grade systemic symptoms 2). Ultimately, 4 participants received A, 7 B, 5 C. Although C experienced DLT, none response, malaise. Therefore, although qualified deemed efficacious (MED), discussion study data monitoring board, recruited B/MED. Among doses completed induction, 52.6% (10/19) achieved 21.1% (4/19) achieving (Figure 1A). Dose B/MED specifically yielded rate 69.2% (9/13) 30.8% (4/13) those 52.9% (9/17) 23.5% (4/17) among this dose. expanded (pTregs) flow cytometry, defined >2-fold increase pTregs (out CD4+ lymphocytes) compared pretreatment 1B). Excluding without having pTreg (given lack regarding they later timepoints), 67% (2/3) 100% (16/16) B/MED, (4/4) 1B Supplementary (10/10) responders 92% (12/13) nonresponders. Most (86%, 19/22) (and 4), most commonly occurring 4. increased absolute count (imputed using lymphocyte count), but pTcon did not significantly change (data shown). Greater seen than (P < .001), difference observed between 1C). No nonresponders In phosphorylated STAT5 (pSTAT5; induced upon receptor activation) expression dose-dependent manner pTcons 1D). pSTAT5 greater .02), trend nonresponder .08) interpret these findings suggest unwanted could explain nonresponse patients. mucosa, there strong diminished (mTregs) nonresponders, both scope .06) 1E). Expansion mTregs (defined >1.2 fold 1) neither required nor sufficient for 1F demonstrate identified MED highest C), despite DLTs, result associated enhanced pTcons. weeks resulted improved participants, yielding par established biologic therapies. pTregs, pTcons, nearly regardless response. found along IL2. include target tissue show mTreg necessary Trial limitations placebo arm, small sample size, central/blinded reading images. Our results support modality its evaluation larger trials. ClinicalTrials.gov, Number NCT02200445 Low-Dose Study Group: Matthew Hamilton, Jared Barends, Madeline Carrellas, Katherine Freer, Jordan Gringauz, Julia Green, Noah Herwood, Jonathan Hurtado, Ryan Kelly, Jennifer Mitri, Caroline Rourke, Gwen Saccocia, Sydney Whitcomb, Enju Liu, David Klatzmann, Punyanganie de Silva, Francis Farraye, Joseph Feuerstein, Alan Moss, Samir Shah, Joshua R. Korzenik, Athos Bousvaros, John Koreth, Robert Soiffer, Jerome Ritz, Tanya Logvinenko, Ashwin Ananthakrishnan, Hans Herfarth. authors would also like acknowledge Prometheus supplying drug trial. Jessica Allegretti, MD, MPH (Investigation: Lead; Supervision: Supporting; Writing – original draft: Equal; review & editing: Equal). Vanessa Mitsialis, MD (Formal analysis: Lead). James Canavan, PhD (Conceptualization: Methodology: Supporting). Scott Snapper, 1Patient DemographicsPatient CharacteristicsDose ADose BDose CDose B/MEDn47510Male, n (%)2 (50)4 (57.1)4 (80)8 (80)White, (%)4 (100)7 (100)5 (100)9 (90)Average age, y36.74346.638.5Average duration, y6.759.3212.610.4Average baseline score8.58.78.89.2Average ± SD CRP, mg/L22.7 31.87.1 6.53.0 1.82.9 2.8Average fecal calprotectin, μg/g stool1422 1066297.6 150373.2 185319.3 327.1Prednisone use baseline, (50)3 (43)1 (20)7 (70)Average prior biologics/small molecules used2.52.41.82.8Failure more biologics (%)3 (75)6 (86)4 (80)9 (90)Disease extent: proctitis, n1100Disease left-sided, n2537Disease pancolitis, n1123CRP, C-reactive protein; SD, standard deviation. Open table new tab 2Peripheral Mucosal Numbers Across All Recruited PatientsDosePTBaseline (D0) % lymphocytesMax expansion, over D0pTreg achievedFirst timepoint >2 D0Timepoint max pTregexpansionScope mean lymphocytesScope lymphocytesColonic changeResponderParticipationPT25.02.8YesW4W830.631.71.0NoCompleted studyDose APT3PT4PT55.1 5.15.01.2 1.32.9No YesNANAW2W4W6W4Not available analysis17.219.9NA20.320.2NA1.21.0No YesWithdrew W6 Completed BPT6PT7PT8PT9PT10PT11PT124.2 4.8 4.6 4.73.411.07.21.9 8.2 2.9 4.5 7.1 2.23.2No Yes YesNAW2W1W2W2W2W4W2W2W1W4W8W4W49.03.820.8 21.0 13.7 19.715.4NA6.6NA26.0 45.1 24.211.0NA1.7NA1.2 3.3 1.20.7NoYes NoYes yesWithdrew W6Completed Withdrew W2 studyMEDPT18PT19PT20PT21PT22PT23PT24PT25PT26PT276.87.510.15.4 8.8 8.5 5.8 6.1 3.96.42.8 5.5 3.8 4.7 5.4 7.13.6Yes YesW2W2W1W2W4W1W1W2W1W1W2W6W8W6W4W2W4W4W2W413.16.27.028.319.8 8.933.2 6.511.818.0NA5.814.7 29.525.2 7.115.2 11.816.1NANA0.9 2.1 1.0 1.3 0.8 0.5 1.81.4NANo NoNoWithdrew W4 studyWithdrew W8 W6Dose CPT13PT14PT15PT16PT174.09.311.910.07.34.2 3.6 3.62.9Yes YesW1W2NAW1W1W2W8W1W2W414.9 20.822.4 9.731.314.641.3NA8.2NA1.02.0NA0.8NANo NoCompleted W2Completed W5D0, day 0; max, maximum; NA, applicable; PT, patient; W, week. D0,