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The Effect of Low-dose Interleukin-2 on the Immune Landscape of Human Atherosclerotic Plaques at Single Cell Resolution. (ELLIPSE)

Primary Purpose

TIA, Carotid Artery Plaque, Carotid Atherosclerosis

Status
Not yet recruiting
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Interleukin-2 [IL-2]
Standard care - Carotid Endarterectomy
Sponsored by
Cambridge University Hospitals NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for TIA focused on measuring Interleukin-2, IL-2, TIA, Carotid Stenosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Presence of carotid stenosis on either ultrasound or CT scan. Planned to undergo carotid endarterectomy. Exclusion Criteria: Autoimmune disease Any regular immunosuppressive treatment [Inhaled or topical steroids are permissible] Modified Rankin Scale score of ≥4 at screening Known active hepatic disease or alanine aminotransferase (ALT) > 2xULN Severe chronic kidney disease (defined as eGFR < 30 ml/min/1.73m2) Allergy or intolerance to aldesleukin Signs or symptoms of active infection History of human immunodeficiency virus (HIV), hepatitis B or C Current malignancy requiring active treatment Vaccine within 4 weeks prior to screening or plans for vaccination during study period Women of child-bearing potential and pregnancy Women who are breast-feeding Clinically relevant medical or surgical conditions that, in the opinion of the

Sites / Locations

  • Addenbrookes Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Low dose interleukin-2

Control

Arm Description

Commercially available aldesleukin with a UK marketing authorisation will be used and will be initially prepared as per SmPC.

Standard of care treatment

Outcomes

Primary Outcome Measures

Difference in gene expression in Tregs
Comparing differential gene expression using scRNA-seq technologies, from isolated Tregs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score)

Secondary Outcome Measures

Difference in gene expression in Teff cells.
Comparing differential gene expression using scRNA-seq technologies, from isolated Teffs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score)
Immune cell gene signature, in plaque and blood.
Difference in immune cell gene signature will be compared using scRNA-seq in both plaque and blood samples, and further compared between IL-2 and control groups. Comparative analysis will be completed using gene set enrichment analysis (Enrichment Score).
Difference in gene expression patterns in Treg & Teff cells.
Comparison between Treg and Teff cells collected at baseline and day of surgery will be compared between IL-2 and control groups. Differential gene expression will be assessed using standard techniques (Z-Score)

Full Information

First Posted
June 14, 2023
Last Updated
August 2, 2023
Sponsor
Cambridge University Hospitals NHS Foundation Trust
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1. Study Identification

Unique Protocol Identification Number
NCT05975554
Brief Title
The Effect of Low-dose Interleukin-2 on the Immune Landscape of Human Atherosclerotic Plaques at Single Cell Resolution.
Acronym
ELLIPSE
Official Title
The Effect of Low-dose Interleukin-2 on the Immune Landscape of Human Atherosclerotic Plaques at Single Cell Resolution.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
August 26, 2023 (Anticipated)
Primary Completion Date
August 1, 2025 (Anticipated)
Study Completion Date
September 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Cambridge University Hospitals NHS Foundation Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The goal of this clinical trail is to compare the differences in carotid plaque Treg cells' gene signature for activation, proliferation, and suppressive function using scRNA-seq in patients treated with IL-2 compared to control.
Detailed Description
Up till now our Lab has looked at Tregs and immune cells in the blood. The question remains whether low dose IL-2 can have the desired effect on Tregs in atherosclerotic plaques where they could alter the pathophysiology and potentially clinical outcomes for patients. Up until recently, the cellular composition and cell-specific expression patterns of human atherosclerotic plaques remained elusive. However, recent breakthroughs studies using scRNA-seq, CITE-seq, and single-cell ATAC-seq on human carotid plaques have offered important insight into plaque composition, cell heterogeneity, and cell-cell interactions giving new perspectives on mechanisms of disease. The next logical stage is to use this new insight and powerful biological tool to assist in drug development for patients. Therefore, the aims of the study are: To assess if low dose IL-2, given systemically to patients at our proposed dose, can alter Tregs in atherosclerotic plaques (the disease tissue) to exhibit a proliferating, activated, and immunosuppressive phenotype To assess if modulating plaque Tregs can cause a shift in the plaque immune landscape to a less inflammatory phenotype To study the relationship between plaque and circulating immune cells after systemic immune modulation

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
TIA, Carotid Artery Plaque, Carotid Atherosclerosis
Keywords
Interleukin-2, IL-2, TIA, Carotid Stenosis

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Masking Description
Analysis blinded
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Low dose interleukin-2
Arm Type
Experimental
Arm Description
Commercially available aldesleukin with a UK marketing authorisation will be used and will be initially prepared as per SmPC.
Arm Title
Control
Arm Type
Active Comparator
Arm Description
Standard of care treatment
Intervention Type
Drug
Intervention Name(s)
Interleukin-2 [IL-2]
Intervention Description
5 sequential days of treatment (1.5MIU/day subcutaneously)
Intervention Type
Procedure
Intervention Name(s)
Standard care - Carotid Endarterectomy
Intervention Description
Standard care for patients with carotid stenosis undergoing carotid endarterectomy
Primary Outcome Measure Information:
Title
Difference in gene expression in Tregs
Description
Comparing differential gene expression using scRNA-seq technologies, from isolated Tregs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score)
Time Frame
Time of surgery
Secondary Outcome Measure Information:
Title
Difference in gene expression in Teff cells.
Description
Comparing differential gene expression using scRNA-seq technologies, from isolated Teffs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score)
Time Frame
Time of surgery
Title
Immune cell gene signature, in plaque and blood.
Description
Difference in immune cell gene signature will be compared using scRNA-seq in both plaque and blood samples, and further compared between IL-2 and control groups. Comparative analysis will be completed using gene set enrichment analysis (Enrichment Score).
Time Frame
Time of surgery
Title
Difference in gene expression patterns in Treg & Teff cells.
Description
Comparison between Treg and Teff cells collected at baseline and day of surgery will be compared between IL-2 and control groups. Differential gene expression will be assessed using standard techniques (Z-Score)
Time Frame
Baseline and at time of surgery
Other Pre-specified Outcome Measures:
Title
Other immune cell and vascular smooth muscle cell gene expression
Description
As per primary outcome measure but in immune cells and vascular smooth muscle cells (excluding Treg & Teff cells). Differential gene expression will be assessed using standard techniques (Z-Score)
Time Frame
Time of surgery
Title
Ligand-receptor interactions.
Description
Differential regulation of ligand-receptor interactions between control and IL-2 treated cells will be identified by comparing single-cell/single-cell ligand-receptor interaction scores for the two groups. This measure is descriptive in nature.
Time Frame
Time of surgery
Title
T-Cell receptor profile
Description
Difference in TCR clonality in plaques between the two groups will be assessed from clonotypes based on identical V-J gene usage and identical CDR3 junctions.
Time Frame
Time of surgery
Title
Inflammatory pathway activation.
Description
Activation of inflammatory pathways both at plaque and systemic level. Assess for enrichment of genes involved in inflammatory pathways - enrichment score.
Time Frame
Time of surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Presence of carotid stenosis on either ultrasound or CT scan. Planned to undergo carotid endarterectomy. Exclusion Criteria: Autoimmune disease Any regular immunosuppressive treatment [Inhaled or topical steroids are permissible] Modified Rankin Scale score of ≥4 at screening Known active hepatic disease or alanine aminotransferase (ALT) > 2xULN Severe chronic kidney disease (defined as eGFR < 30 ml/min/1.73m2) Allergy or intolerance to aldesleukin Signs or symptoms of active infection History of human immunodeficiency virus (HIV), hepatitis B or C Current malignancy requiring active treatment Vaccine within 4 weeks prior to screening or plans for vaccination during study period Women of child-bearing potential and pregnancy Women who are breast-feeding Clinically relevant medical or surgical conditions that, in the opinion of the
Facility Information:
Facility Name
Addenbrookes Hospital
City
Cambridge
State/Province
Cambridgeshire
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tian Zhao, MBBS, PhD
Phone
01223768678
Email
Txz20@cam.ac.uk

12. IPD Sharing Statement

Learn more about this trial

The Effect of Low-dose Interleukin-2 on the Immune Landscape of Human Atherosclerotic Plaques at Single Cell Resolution.

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