Low-dose i nterleukin 2 for the reduction of v ascular inflammati o n in acute corona ry syndromes (IVORY): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase II clinical trial

Rouchelle Sriranjan, Tian Xiao Zhao, Jason Tarkin, Annette Hubsch, Joanna Helmy, Evangelia Vamvaka, Navazh Jalaludeen, Simon Bond, Stephen P Hoole, Philip Knott, Samantha Buckenham, Victoria Warnes, Nick Bird, Heok Cheow, Heike Templin, Paul Cacciottolo, James H F Rudd, Ziad Mallat, Joseph Cheriyan, Rouchelle Sriranjan, Tian Xiao Zhao, Jason Tarkin, Annette Hubsch, Joanna Helmy, Evangelia Vamvaka, Navazh Jalaludeen, Simon Bond, Stephen P Hoole, Philip Knott, Samantha Buckenham, Victoria Warnes, Nick Bird, Heok Cheow, Heike Templin, Paul Cacciottolo, James H F Rudd, Ziad Mallat, Joseph Cheriyan

Abstract

Introduction: Inflammation plays a critical role in the pathogenesis of atherosclerosis, the leading cause of ischaemic heart disease (IHD). Studies in preclinical models have demonstrated that an increase in regulatory T cells (Tregs), which have a potent immune modulatory action, led to a regression of atherosclerosis. The Low-dose InterLeukin 2 (IL-2) in patients with stable ischaemic heart disease and Acute Coronary Syndromes (LILACS) study, established the safety of low-dose IL-2 and its biological efficacy in IHD. The IVORY trial is designed to assess the effects of low-dose IL-2 on vascular inflammation in patients with acute coronary syndromes (ACS).

Methods and analysis: In this study, we hypothesise that low-dose IL-2 will reduce vascular inflammation in patients presenting with ACS. This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Patients will be recruited across two centres, a district general hospital and a tertiary cardiac centre in Cambridge, UK. Sixty patients with ACS (unstable angina, non-ST elevation myocardial infarction or ST elevation myocardial infarction) with high-sensitivity C reactive protein (hsCRP) levels >2 mg/L will be randomised to receive either 1.5×106 IU of low-dose IL-2 or placebo (1:1). Dosing will commence within 14 days of admission. Dosing will comprise of an induction and a maintenance phase. 2-Deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography/CT (PET/CT) scans will be performed before and after dosing. The primary endpoint is the change in mean maximum target to background ratios (TBRmax) in the index vessel between baseline and follow-up scans. Changes in circulating T-cell subsets will be measured as secondary endpoints of the study. The safety and tolerability of extended dosing with low-dose IL-2 in patients with ACS will be evaluated throughout the study.

Ethics and dissemination: The Health Research Authority and Health and Care Research Wales, UK (19/YH/0171), approved the study. Written informed consent is required to participate in the trial. The results will be reported through peer-reviewed journals and conference presentations.

Trial registration number: NCT04241601.

Keywords: cardiology; cardiovascular imaging; clinical trials; immunology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Summary of trial design. 18F-FDG, 2-deoxy-2-[fluorine-18] fluoro-D-glucose; NSTEMI, non-ST elevation myocardial infarction; PET, positron emission tomography; STEMI, ST elevation myocardial infarction.
Figure 2
Figure 2
IVORY trial visits—timeline and assessments. ECHO, echocardiogram; 18F-FDG, 2-deoxy-2-[fluorine-18] fluoro-D-glucose; IMP, investigational medical product; PET, positron emission tomography.
Figure 3
Figure 3
Lymphocyte subset analysis: A - Phenotypic characterisation of T cell subsets by flow cytometry; B -Antibodies used in fluorescence-activated cell sorting (FACS) analysis of T-cell subsets.
Figure 4
Figure 4
Analysis methods used to quantify vascular inflammation in the index vessel. TBR, target to background ratio.

References

    1. Abdolmaleki F, Gheibi Hayat SM, Bianconi V, et al. . Atherosclerosis and immunity: a perspective. Trends Cardiovasc Med 2019;29:363–71. 10.1016/j.tcm.2018.09.017
    1. Ridker PM, Everett BM, Thuren T, et al. . Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31. 10.1056/NEJMoa1707914
    1. Libby P, Everett BM. Novel antiatherosclerotic therapies. Arterioscler Thromb Vasc Biol 2019;39:538–45. 10.1161/ATVBAHA.118.310958
    1. Kobiyama K, Saigusa R, Ley K. Vaccination against atherosclerosis. Curr Opin Immunol 2019;59:15–24. 10.1016/j.coi.2019.02.008
    1. Ait-Oufella H, Salomon BL, Potteaux S, et al. . Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006;12:178–80. 10.1038/nm1343
    1. Sharma M, Schlegel MP, Afonso MS, et al. . Regulatory T cells license macrophage pro-resolving functions during atherosclerosis regression. Circ Res 2020;127:335–53. 10.1161/CIRCRESAHA.119.316461
    1. Xiao J, Yu K, Li M, et al. . The IL-2/Anti-IL-2 complex attenuates cardiac ischaemia-reperfusion injury through expansion of regulatory T cells. Cell Physiol Biochem 2017;44:1810–27. 10.1159/000485818
    1. Hofmann U, Beyersdorf N, Weirather J, et al. . Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation 2012;125:1652–63. 10.1161/CIRCULATIONAHA.111.044164
    1. Matsumoto K, Ogawa M, Suzuki J-ichi, et al. . Regulatory T lymphocytes attenuate myocardial infarction-induced ventricular remodeling in mice. Int Heart J 2011;52:382–7. 10.1536/ihj.52.382
    1. Dobaczewski M, Xia Y, Bujak M, et al. . Ccr5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells. Am J Pathol 2010;176:2177–87. 10.2353/ajpath.2010.090759
    1. Yu X, Newland SA, Zhao TX, et al. . Innate Lymphoid Cells Promote Recovery of Ventricular Function After Myocardial Infarction. J Am Coll Cardiol 2021;78:1127–42. 10.1016/j.jacc.2021.07.018
    1. Wigren M, Björkbacka H, Andersson L, et al. . Low levels of circulating CD4+Foxp3+ T cells are associated with an increased risk for development of myocardial infarction but not for stroke. Arterioscler Thromb Vasc Biol 2012;32:2000–4. 10.1161/ATVBAHA.112.251579
    1. Cheng X, Yu X, Ding Y-J, et al. . The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 2008;127:89–97. 10.1016/j.clim.2008.01.009
    1. Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019;124:315–27. 10.1161/CIRCRESAHA.118.313591
    1. Han S-fang, Liu P, Zhang W, et al. . The opposite-direction modulation of CD4+CD25+ Tregs and T helper 1 cells in acute coronary syndromes. Clin Immunol 2007;124:90–7. 10.1016/j.clim.2007.03.546
    1. Ammirati E, Cianflone D, Banfi M, et al. . Circulating CD4+CD25hiCD127lo regulatory T-cell levels do not reflect the extent or severity of carotid and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:1832–41. 10.1161/ATVBAHA.110.206813
    1. Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 2015;15:283–94. 10.1038/nri3823
    1. Zhao TX, Newland SA, Mallat Z. 2019 ATVB Plenary Lecture: Interleukin-2 Therapy in Cardiovascular Disease: The Potential to Regulate Innate and Adaptive Immunity. Arterioscler Thromb Vasc Biol 20202020;40:853–64. 10.1161/ATVBAHA.119.312287
    1. Sakaguchi S, Sakaguchi N, Asano M, et al. . Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64.
    1. Vang KB, Yang J, Mahmud SA, et al. . Il-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J Immunol 2008;181:3285–90. 10.4049/jimmunol.181.5.3285
    1. Humrich JY, von Spee-Mayer C, Siegert E, et al. . Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann Rheum Dis 2015;74:791–2. 10.1136/annrheumdis-2014-206506
    1. Matsuoka K-ichi, Koreth J, Kim HT, et al. . Low-Dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 2013;5:179ra43–79. 10.1126/scitranslmed.3005265
    1. He J, Zhang X, Wei Y, et al. . Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med 2016;22:991–3. 10.1038/nm.4148
    1. Koreth J, Matsuoka K-ichi, Kim HT, et al. . Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011;365:2055–66. 10.1056/NEJMoa1108188
    1. Rosenzwajg M, Lorenzon R, Cacoub P, et al. . Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis 2019;78:209–17. 10.1136/annrheumdis-2018-214229
    1. Zhao T, Sriranjan R, Tuong Z. Regulatory T cell response to low-dose IL-2 in ischemic heart disease.. NEJM evidence 2021;1. 10.1056/EVIDoa2100009
    1. Cheng VY, Slomka PJ, Le Meunier L, et al. . Coronary arterial 18F-FDG uptake by fusion of PET and coronary CT angiography at sites of percutaneous stenting for acute myocardial infarction and stable coronary artery disease. J Nucl Med 2012;53:575–83. 10.2967/jnumed.111.097550
    1. Tarkin JM, Joshi FR, Evans NR, et al. . Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging. J Am Coll Cardiol 2017;69:1774–91. 10.1016/j.jacc.2017.01.060
    1. Folco EJ, Sheikine Y, Rocha VZ, et al. . Hypoxia but not inflammation augments glucose uptake in human macrophages: implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-D-glucose positron emission tomography. J Am Coll Cardiol 2011;58:603–14. 10.1016/j.jacc.2011.03.044
    1. Ogawa M, Nakamura S, Saito Y, et al. . What can be seen by 18F-FDG PET in atherosclerosis imaging? the effect of foam cell formation on 18F-FDG uptake to macrophages in vitro. J Nucl Med 2012;53:55–8. 10.2967/jnumed.111.092866
    1. Tawakol A, Migrino RQ, Bashian GG, et al. . In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol 2006;48:1818–24. 10.1016/j.jacc.2006.05.076
    1. Rudd JHF, Myers KS, Bansilal S, et al. . Atherosclerosis inflammation imaging with 18F-FDG PET: carotid, iliac, and femoral uptake reproducibility, quantification methods, and recommendations. J Nucl Med 2008;49:871–8. 10.2967/jnumed.107.050294
    1. Tarkin JM, Joshi FR, Rudd JHF. Pet imaging of inflammation in atherosclerosis. Nat Rev Cardiol 2014;11:443–57. 10.1038/nrcardio.2014.80
    1. Fayad ZA, Mani V, Woodward M, et al. . Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011;378:1547–59. 10.1016/S0140-6736(11)61383-4
    1. Elkhawad M, Rudd JHF, Sarov-Blat L, et al. . Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc Imaging 2012;5:911–22. 10.1016/j.jcmg.2012.02.016
    1. Mäki-Petäjä KM, Elkhawad M, Cheriyan J. Anti-Tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis.. Circulation 2012;120410. 10.1161/CIRCULATIONAHA.112.120410
    1. Tahara N, Kai H, Ishibashi M, et al. . Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2006;48:1825–31. 10.1016/j.jacc.2006.03.069
    1. Figueroa AL, Abdelbaky A, Truong QA, et al. . Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future cv events. JACC Cardiovasc Imaging 2013;6:1250–9. 10.1016/j.jcmg.2013.08.006
    1. Tawakol A, Singh P, Rudd JHF, et al. . Effect of treatment for 12 weeks with rilapladib, a lipoprotein-associated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18F-fluorodeoxyglucose-positron emission tomography imaging. J Am Coll Cardiol 2014;63:86–8. 10.1016/j.jacc.2013.07.050
    1. Bucerius J, Hyafil F, Verberne HJ, et al. . Position paper of the cardiovascular Committee of the European association of nuclear medicine (EANM) on PET imaging of atherosclerosis. Eur J Nucl Med Mol Imaging 2016;43:780–92. 10.1007/s00259-015-3259-3
    1. O'Donoghue ML, Braunwald E, White HD. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA 2014;312:1006–15. 10.1001/jama.2014.11061
    1. Schwartz GG, Olsson AG, Abt M, et al. . Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089–99. 10.1056/NEJMoa1206797
    1. , White HD, Held C, et al. , STABILITY Investigators . Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med 2014;370:1702–11. 10.1056/NEJMoa1315878

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren