Regulatory T-Cell Response to Low-Dose Interleukin-2 in Ischemic Heart Disease

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cam.issuedOnline2021-11-22
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dc.contributor.authorZhao, Tian X
dc.contributor.authorSriranjan, Rouchelle
dc.contributor.authorTuong, Zewen
dc.contributor.authorLu, yuning
dc.contributor.authorSage, Andrew
dc.contributor.authorNus, Meritxell
dc.contributor.authorHubsch, Annette
dc.contributor.authorKaloyirou, Fotini
dc.contributor.authorVamvaka, Evangelia
dc.contributor.authorHelmy, Joanna
dc.contributor.authorKostapanos, Michalis
dc.contributor.authorJalaludeen, Navazh
dc.contributor.authorKlatzmann, David
dc.contributor.authorTedgui, Alain
dc.contributor.authorRudd, James
dc.contributor.authorHorton, Sarah
dc.contributor.authorHuntly, Brian
dc.contributor.authorHoole, Stephen
dc.contributor.authorBond, simon
dc.contributor.authorClatworthy, Menna
dc.contributor.authorCheriyan, Joseph
dc.contributor.authorMallat, Ziad
dc.contributor.orcidTuong, Kelvin [0000-0002-6735-6808]
dc.contributor.orcidLu, Yuning [0000-0001-8619-9724]
dc.contributor.orcidSage, Andrew [0000-0001-7255-3497]
dc.contributor.orcidNus Chimeno, Meritxell [0000-0002-6378-8910]
dc.contributor.orcidRudd, James [0000-0003-2243-3117]
dc.contributor.orcidHuntly, Brian [0000-0003-0312-161X]
dc.contributor.orcidBond, Simon [0000-0003-2528-1040]
dc.contributor.orcidClatworthy, Menna [0000-0002-3340-9828]
dc.contributor.orcidMallat, Ziad [0000-0003-0443-7878]
dc.date.accessioned2021-10-22T23:30:23Z
dc.date.available2021-10-22T23:30:23Z
dc.description.abstractBACKGROUND Atherosclerosis is a chronic inflammatory disease of the artery wall. Regulatory T cells (Tregs) limit inflammation and promote tissue healing. Low doses of interleukin (IL)-2 have the potential to increase Tregs, but its use is contraindicated in patients with ischemic heart disease. METHODS In this randomized, double-blind, placebo-controlled, dose-escalation trial, we tested lowdose subcutaneous aldesleukin (recombinant IL-2), given once daily for five consecutive days. In Part A, the primary endpoint was safety, and patients with stable ischemic heart disease were randomized to placebo or to one of 5 dose groups (range 0.3-3.0 x10 6 IU/day). In Part B, patients with acute non-ST elevation myocardial infarction or unstable angina were randomized to placebo or to one of 2 dose groups (1.5 and 2.5 x10 6 IU/day). The coprimary endpoints were safety and the dose required to increase circulating Tregs by 75%. Single-cell RNA-sequencing of circulating immune cells was used to provide mechanistic assessment of the effects of aldesleukin. RESULTS Forty-four patients were randomized in the study, 26 patients in Part A and 18 patients in Part B. In total, 3 patients withdrew prior to dosing; 27 received active treatment, and 14 received placebo. The majority of adverse events were mild. Two serious adverse events occurred, with one occurring after drug administration. In Parts A and B, there was a dosedependent increase in Tregs. In Part B, the estimated dose to achieve a 75% increase in Tregs was 1.46 x10 6 IU (95%CI 1.06 – 1.87). Single-cell RNA-sequencing demonstrated the engagement of distinct pathways and cell-cell interactions. CONCLUSION In this phase 1b/2a study, low-dose IL-2 expanded Tregs without adverse events of major concern. Larger trials are needed to confirm safety and to further evaluate efficacy of lowdose IL-2 as an anti-inflammatory therapy in patients with ischemic heart disease. (Funded by the Medical Research Council and the British Heart Foundation; ClinicalTrials.gov number, NCT03113773)
dc.identifier.doi10.17863/CAM.77239
dc.identifier.issn0028-4793
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/329794
dc.publisherMassachusetts Medical Society
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleRegulatory T-Cell Response to Low-Dose Interleukin-2 in Ischemic Heart Disease
dc.typeArticle
dcterms.dateAccepted2021-10-13
prism.publicationNameNew England Journal of Medicine Evidence
pubs.funder-project-idBritish Heart Foundation (CH/10/001/27642)
pubs.funder-project-idMedical Research Council (MR/N028015/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/N014588/1)
pubs.funder-project-idEPSRC (EP/T017961/1)
pubs.funder-project-idBritish Heart Foundation (CH/10/001/27642)
pubs.funder-project-idMedical Research Council (MR/S035842/1)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (RP-2017-08-ST2-002)
rioxxterms.licenseref.startdate2021-10-13
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1056/EVIDoa2100009
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