Low dose interleukin (IL)-2 in patients with a recent acute coronary syndrome
Lead Research Organisation:
University of Cambridge
Department Name: Medicine
Abstract
Cardiovascular diseases (CVD) are the leading cause of mortality in Europe (5 million deaths per year) and in the World (19 million deaths) and strike both low- and middle-income countries as well as affluent countries. CVD cost the European Union's economy 196 billion euros in 2009. CVD mostly result from atherosclerosis, the build-up of fatty plaques in the walls of our arteries, which is the cause of heart attacks and strokes. The accumulation of cholesterol in the arteries leads to subtle chemical modifications making it recognised by our immune system as a strange 'non-self' material. The activated immune system sends white blood cells to try and clear away the fatty material, but this can cause the artery to become inflamed and make the disease worse. More than a decade of research on the mechanisms of atherosclerosis has led to the identification by our group of some types of white blood cells that are helpful and can slow down the disease. Current treatments of atherosclerosis do not target the immune system. Thus, harnessing the helpful white blood cells might give us new effective treatments to combat the build up of fatty plaques in our arteries.
A substance called interleukin (IL)-2 is licensed for use at high dose in cancers of the kidney. Interestingly, recent research indicates that low doses of IL-2 (20 to 100-fold lower than the doses used in cancer) selectively stimulate and expand the population of helpful white blood cells. We want to harness this new knowledge for the development of new treatments that stimulate the cells that protect our arteries without stimulating the damaging ones, and re-purpose IL-2 for the treatment of cardiovascular diseases. Here, we will test the hypothesis that treatment of patients with low doses of IL-2 will increase the population of helpful white blood cells to reduce the activation of the harmful ones and limit their detrimental effects on our arteries. We expect this new treatment strategy to have major impact on both the individual and societal levels. The project will be accomplished by a very experienced team of scientists and clinicians, who are world leaders in this field, working in the University of Cambridge, UK, one of the best scientific environment worldwide.
A substance called interleukin (IL)-2 is licensed for use at high dose in cancers of the kidney. Interestingly, recent research indicates that low doses of IL-2 (20 to 100-fold lower than the doses used in cancer) selectively stimulate and expand the population of helpful white blood cells. We want to harness this new knowledge for the development of new treatments that stimulate the cells that protect our arteries without stimulating the damaging ones, and re-purpose IL-2 for the treatment of cardiovascular diseases. Here, we will test the hypothesis that treatment of patients with low doses of IL-2 will increase the population of helpful white blood cells to reduce the activation of the harmful ones and limit their detrimental effects on our arteries. We expect this new treatment strategy to have major impact on both the individual and societal levels. The project will be accomplished by a very experienced team of scientists and clinicians, who are world leaders in this field, working in the University of Cambridge, UK, one of the best scientific environment worldwide.
Technical Summary
Need: Coronary artery disease (CAD), caused by atherosclerosis, carries a substantial risk of morbidity/mortality due to atherosclerotic plaque disruption, which leads to severe ischemic cardiac events, called acute coronary syndromes (ACS). The latter define a spectrum of clinical manifestations, including unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). The occurrence of ACS (which may represent the first manifestation of CAD) further enhances the risk of recurrence and death. Although rates of in-hospital complications have dropped significantly, late consequences of ACS are largely underestimated and unrecognised with 5-year rates of death in the range of 20% despite the best of current therapeutic management [Fox KA, Eur Heart J 2010]. Out-of-hospital adverse events result from deleterious post-ischemic cardiac remodeling and progression of CAD, the determinants of which are instigated during the first months following the index event.
Rationale: Immune dys-regulation, and more particularly defective regulatory T lymphocytes (Tregs), plays a central role in the pathophysiology of atherosclerosis and post-ischemic injury (see section 5 below). Unfortunately however, Tregs escape targeting by all of the current or tested therapies in CAD patients. Interleukin (IL)2 is essential for the development, survival, and function of Tregs. Interestingly, recombinant IL2 is available for drug re-purposing, and low dose (ld)-IL2 therapy preferentially induces Treg expansion in humans.
Solution: Enhance Tregs through supplementation with ld-IL2 to suppress cardiovascular (CV) inflammation, with the aim to ultimately promote tissue repair and limit adverse CV events.
Main question addressed here (which will form a go/no-go milestone for potential phase III clinical outcome trials): Does ld-IL2 safely enhance Treg levels and reduce vascular inflammation in patients with a recent ACS?
Rationale: Immune dys-regulation, and more particularly defective regulatory T lymphocytes (Tregs), plays a central role in the pathophysiology of atherosclerosis and post-ischemic injury (see section 5 below). Unfortunately however, Tregs escape targeting by all of the current or tested therapies in CAD patients. Interleukin (IL)2 is essential for the development, survival, and function of Tregs. Interestingly, recombinant IL2 is available for drug re-purposing, and low dose (ld)-IL2 therapy preferentially induces Treg expansion in humans.
Solution: Enhance Tregs through supplementation with ld-IL2 to suppress cardiovascular (CV) inflammation, with the aim to ultimately promote tissue repair and limit adverse CV events.
Main question addressed here (which will form a go/no-go milestone for potential phase III clinical outcome trials): Does ld-IL2 safely enhance Treg levels and reduce vascular inflammation in patients with a recent ACS?
Planned Impact
CV diseases (CVD) are the leading cause of mortality in Europe (5 million deaths per year) and in the World (19 million deaths) and strike both low- and middle-income countries as well as affluent countries.
CVD cost the European Union's economy 196 billion euros in 2009. There has been considerable progress in the treatment and prevention of CVD. Yet, current statistics show that mortality after an acute coronary syndrome remains high, with 5-year rates in the range of 20%, and that the overwhelming majority of these deaths occur after hospital discharge, indicating that these deaths occur from the consequences of myocardial injury despite modern therapy.
Therefore, there is urgent need to develop novel approaches to treat CVD. The novel concept and therapeutic strategy outlined in the present project will target a selective immune cell subset, Treg cells, in a specific clinical setting, and will have the potential to profoundly impact the management of patients with CAD.
The project will have major impact on both the individual and societal levels.
1. Impact on providing a new therapy, i.e., low-dose interleukin-2 (Ldl-IL2), that generates advances in clinical practice: The chosen therapeutic strategy has no equivalent in the current armamentarium of drugs used to treat the disease. We anticipate that the proposed strategy can be combined with currently available and validated ones. We also anticipate that the proposed new therapy will ultimately lead to more than 30% reduction in cardiovascular events and morbidity on top of currently available therapeutic strategies.
2. An original aspect is that our therapeutic concept can additionally target immune dysregulation associated with co-morbidities. The presence of such co-morbidities (e.g., diabetes) in CAD patients more than doubles the risk of coronary events, an excess risk that is resistant to treatment. Treg alteration is involved in the pathophysiology of rheumatologic diseases and diabetes, strongly suggesting additional benefit from a our novel ld-IL2 therapy.
3. Impact on outcome for individual patients and for health care systems: We expect our ld-IL2 therapy will have selective effects on specific stages of the disease process and may therefore induce long-term protection and impact patient management on the individual level. Time-limited therapeutic interventions that provide long-term protection are eagerly needed. We believe that the treatment regimens proposed in the present project (a few s.c. injection of ld-IL2) will substantially lower the risk of treatment failure due to non-compliance, in comparison with daily drug intake for other therapies, and will very effectively improve the treatment of patients with CVD. Finally, we anticipate that interference with this novel and critical disease pathway will provide substantial additional clinical and economic benefit. If we show that a few injections of ld-IL2 reduce vascular inflammation in patients with acute coronary syndromes, we will have identified a novel, simple, cost-effective and ground-breaking strategy to limit the burden of CVD. Indeed, the cost of an 8-week treatment with ld-IL-2 is expected to be substantially lower than the cost of currently tested therapeutics, highlighting innovative and cost effective therapeutic approaches.
4. The study will provide essential clinical target validation and the applicants plan to go on to identify IL-2 analogues or small molecules with preferential activity for Treg that could result in strong composition of matter claims which could be licensed to a commercial partner. The study will likely generate a valuable data package which may include patents but will include essential confidential information useful to a commercial partner so we believe a commercial partner would chose to work with Cambridge to exploit IL-2 for ACS rather than work independently.
CVD cost the European Union's economy 196 billion euros in 2009. There has been considerable progress in the treatment and prevention of CVD. Yet, current statistics show that mortality after an acute coronary syndrome remains high, with 5-year rates in the range of 20%, and that the overwhelming majority of these deaths occur after hospital discharge, indicating that these deaths occur from the consequences of myocardial injury despite modern therapy.
Therefore, there is urgent need to develop novel approaches to treat CVD. The novel concept and therapeutic strategy outlined in the present project will target a selective immune cell subset, Treg cells, in a specific clinical setting, and will have the potential to profoundly impact the management of patients with CAD.
The project will have major impact on both the individual and societal levels.
1. Impact on providing a new therapy, i.e., low-dose interleukin-2 (Ldl-IL2), that generates advances in clinical practice: The chosen therapeutic strategy has no equivalent in the current armamentarium of drugs used to treat the disease. We anticipate that the proposed strategy can be combined with currently available and validated ones. We also anticipate that the proposed new therapy will ultimately lead to more than 30% reduction in cardiovascular events and morbidity on top of currently available therapeutic strategies.
2. An original aspect is that our therapeutic concept can additionally target immune dysregulation associated with co-morbidities. The presence of such co-morbidities (e.g., diabetes) in CAD patients more than doubles the risk of coronary events, an excess risk that is resistant to treatment. Treg alteration is involved in the pathophysiology of rheumatologic diseases and diabetes, strongly suggesting additional benefit from a our novel ld-IL2 therapy.
3. Impact on outcome for individual patients and for health care systems: We expect our ld-IL2 therapy will have selective effects on specific stages of the disease process and may therefore induce long-term protection and impact patient management on the individual level. Time-limited therapeutic interventions that provide long-term protection are eagerly needed. We believe that the treatment regimens proposed in the present project (a few s.c. injection of ld-IL2) will substantially lower the risk of treatment failure due to non-compliance, in comparison with daily drug intake for other therapies, and will very effectively improve the treatment of patients with CVD. Finally, we anticipate that interference with this novel and critical disease pathway will provide substantial additional clinical and economic benefit. If we show that a few injections of ld-IL2 reduce vascular inflammation in patients with acute coronary syndromes, we will have identified a novel, simple, cost-effective and ground-breaking strategy to limit the burden of CVD. Indeed, the cost of an 8-week treatment with ld-IL-2 is expected to be substantially lower than the cost of currently tested therapeutics, highlighting innovative and cost effective therapeutic approaches.
4. The study will provide essential clinical target validation and the applicants plan to go on to identify IL-2 analogues or small molecules with preferential activity for Treg that could result in strong composition of matter claims which could be licensed to a commercial partner. The study will likely generate a valuable data package which may include patents but will include essential confidential information useful to a commercial partner so we believe a commercial partner would chose to work with Cambridge to exploit IL-2 for ACS rather than work independently.
Publications
Sriranjan R
(2021)
Atherosclerosis imaging using PET: Insights and applications.
Nus M
(2016)
Immune-mediated mechanisms of atherosclerosis and implications for the clinic.
in Expert review of clinical immunology
Mallat Z
(2022)
The why and how of adaptive immune responses in ischemic cardiovascular disease.
in Nature cardiovascular research
Description | British Heart Foundation Centre of Excellence Pump-Priming Award |
Amount | £92,352 (GBP) |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2016 |
End | 03/2017 |
Description | Comprehensive analysis of plaque infiltrating ILC2 in human cardiovascular disease |
Amount | £257,957 (GBP) |
Funding ID | PG/21/10816 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2022 |
End | 02/2025 |
Description | Low dose interleukin (IL)-2 in patients with a recent acute coronary syndrome |
Amount | £2,315,261 (GBP) |
Funding ID | MR/N028015/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start |
Description | THE EFFECT OF LOW-DOSE INTERLEUKIN-2 ON HUMAN ATHEROSCLEROTIC PLAQUE IMMUNE CELLS AT SINGLE CELL RESOLUTION |
Amount | £191,476 (GBP) |
Organisation | Heart Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2022 |
End | 03/2024 |
Description | The effect of Low-Dose Interleukin-2 on the immune landscape of human atherosclerotic plaques at single cell resolution |
Amount | £64,895 (GBP) |
Organisation | British Medical Association (BMA) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2022 |
End | 09/2024 |
Description | The effect of low-dose interleukin-2 on atherosclerotic plaque immune cells in patients undergoing carotid endarterectomy |
Amount | £29,950 (GBP) |
Funding ID | SGL025\1071 |
Organisation | Academy of Medical Sciences (AMS) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2022 |
End | 01/2024 |
Description | Type-2 innate lymphoid cells in the control of the immune atherogenic response to high fat diet |
Amount | £196,387 (GBP) |
Funding ID | PG/15/99/31865 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2016 |
End | 03/2018 |
Description | Hafid Ait-Oufella |
Organisation | National Institute of Health and Medical Research (INSERM) |
Department | INSERM U970 (Paris Cardiovascular Research Centre) |
Country | France |
Sector | Academic/University |
PI Contribution | Collaboration on the role of the immune system in cardiovascular disease |
Collaborator Contribution | Collaboration on the role of the immune system in cardiovascular disease |
Impact | Many peer-reviewed publications |
Start Year | 2010 |
Description | James Rudd |
Organisation | University of Cambridge |
Department | Division of Cardiovascular Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration in imaging vascular inflammation |
Collaborator Contribution | Collaboration in imaging vascular inflammation |
Impact | Obtention of this MRC grant. Publication of the study protocol |
Start Year | 2016 |
Description | Joseph Cheriyan |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Conducting early phase clinical trials to test immunotherapeutic strategies in cardiovascular disease |
Collaborator Contribution | Conducting early phase clinical trials to test immunotherapeutic strategies in cardiovascular disease |
Impact | Ongoing clinical studies |
Start Year | 2016 |
Description | Menna Clatworthy |
Organisation | University of Cambridge |
Department | Cambridge Institute for Medical Research (CIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Study of immune mechanisms of atherosclerosis |
Collaborator Contribution | Provide genetically modified animals; single cell transcriptomics |
Impact | No ouputs |
Start Year | 2010 |
Description | Stephen S. Hoole |
Organisation | Royal Papworth Hospital NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | Collaboration on clinical trials testing immuno-modulatory therapies in patients with ischaemic heart disease. |
Collaborator Contribution | Collaboration on clinical trials testing immuno-modulatory therapies in patients with ischaemic heart disease. |
Impact | Pending |
Start Year | 2019 |