NIH CCR2 AAA Study

The Washington University

Status and phase: Active, not recruiting; Early Phase 1

Conditions: No Abdominal Aortic Aneurysm (Non-AAA); Abdominal Aortic Aneurysm (AAA)

Treatments: Other: Relationship between radiotracer and CCR2 (Aim 2B); Diagnostic Test: AAA Group (Aim 3A); Other: Ex Vivo Human AAA Specimens (Aim 2A); Diagnostic Test: Non-AAA Group; Diagnostic Test: AAA Group (Aim 3B-Reproducibility)

Study type: Interventional

Funder types: Other

Identifiers

NCT04586452

202008190

Details and patient eligibility

About

Abdominal aortic aneurysm (AAA) is a degenerative vascular disease, which is typically asymptomatic until rupture, resulting in high mortality. AAAs are more prevalent in men over age 65, though rupture is disproportionately higher in women. Due to nonlinear and unpredictable aortic dilatation, it is challenging to predict the AAA rupture using clinical diagnostics based on morphology. No medical therapy is used clinically to treat AAA, and there is an unmet need for clinically translatable, molecular biomarkers of AAA disease activity for surveillance and patient-specific management. The goal of this proposal is to develop a new approach for the diagnosis and targeted therapy of AAA.

Full description

This project addresses the absence of a reliable diagnostic modality and medical therapy to prevent abdominal aortic aneurysm (AAA) growth and rupture in patients, leading to high mortality in those over the age of 65 years old. Due to the pathogenic role of the monocyte chemoattractant protein-1 / C-C chemokine receptor type 2 (MCP-1/CCR2) axis in AAA, we propose to study the ability of 64Cu-DOTA-ECL1i PET/CT to predict the murine AAA rupture and serve as a companion diagnostic to assess CCR2 molecular therapy of murine AAA. We will perform the first-in-patient evaluation of 64Cu-DOTA-ECL1i PET/CT to image and detect AAA inflammation in a preoperative setting and acquire key biological information from AAA specimens collected at the time of open AAA repair, in order to assess the potential of 64Cu-DOTA-ECL1i PET in the management of AAA patients.

Preclinical and clinical research demonstrated that monocyte chemotactic protein-1/ chemokine (C-C motif) receptor 2 (MCP-1/CCR2) plays an important role in the pathogenesis of AAAs. This axis specifically promotes AAA formation and development by mediating the recruitment of circulating LY6Chigh monocytes and infiltration of macrophages, which leads to the degradation of elastic and collagen. In AAA mouse models, the genetic depletion or specific inhibition of CCR2 significantly decreased the production of matrix metalloproteinases (MMPs) and formation of aneurysms, suggesting the potential of CCR2 as a biomarker for AAA imaging and pre-screening for targeted intervention.

We have developed a specific CCR2 binding radiotracer, 64Cu-DOTA-ECL1i, for targeted imaging of CCR2 positive pro-inflammatory monocytes/macrophages, in multiple animal inflammatory models using positron emission tomography (PET). This investigational PET tracer is being used under Exploratory IND 137620 for research imaging studies in human subjects. In patients with inflammatory diseases, 64Cu-DOTA-ECL1i PET revealed specific detection of CCR2+ cells in inflammatory tissues. In a rat AAA model, 64Cu-DOTA-ECL1i PET revealed specific localization within the aneurysm, as well as sensitive detection of CCR2+ inflammatory cells. Human AAA specimens demonstrated specific binding of 64Cu-DOTA-ECL1i to CCR2 by autoradiography. Thus, we hypothesize that 64Cu-DOTA-ECL1i detect CCR2+ cells mediated aneurysmal activity and can be utilized for AAA molecular imaging. We propose to assess the potential of 64Cu-DOTA-ECL1i as a biomarker for AAA patients imaging.

Enrollment: 50 estimated patients

Sex: All

Ages: 40+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 40 years old and above
• With or without active tobacco use
• Asymptomatic patients with known AAAs by CT angiogram (men ≥ 5.5 cm, women ≥ 5.0cm).
• Non-AAA volunteers will have a documented absence of AAA by exam and recent screening ultrasound (US).
• Able to comprehend and willing to follow instructions for the study procedures as called for by the protocol

Exclusion criteria

• Inability to receive and sign informed consent.
• Patients with Stage ≥ 4 chronic renal failure (calculated by modification of diet in renal disease eGFR equation [to minimize confounding imaging variables])
• Documented allergy to iodinated contrast and/or shellfish.
• Patients with an unstable clinical condition that in the opinion of the principal investigators or designee precludes participation in the study.
• Inability to tolerate 60 minutes in a supine position with arms down at sides, as necessary for PET/CT.
• Positive pregnancy test or lactating.
• Other conditions such as symptomatic/recently treated coronary disease, cancer requiring oncologic management, or autoimmune/inflammatory diseases (e.g., rheumatoid arthritis or multiple sclerosis) that are known to have increased associated CCR2 expression.
• Non-AAA volunteers may not carry a diagnosis of aortoiliac occlusive disease, as documented by their treating vascular surgeon, as significantly progressed atherosclerotic disease may demonstrate exaggerated, associated CCR2 expression.

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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50 participants in 5 patient groups

AAA Group (Aim 3A)

Experimental group

Description:

40 (20 men; 20 women) participants with a diagnosis of AAA (above 40 years) will undergo a PET/CT scan prior to their scheduled surgical repair of their condition. The radiotracer, 64Cu-DOTA-ECL1i, will be injected to detect CCR2+ inflammatory cells. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.

Treatment:

Diagnostic Test: AAA Group (Aim 3A)

Non-AAA Group

Experimental group

Description:

10 (5 men; 5 women) participants will have a documented absence of AAA by screening ultrasound that was previously obtained as part of standard of care. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.

Treatment:

Diagnostic Test: Non-AAA Group

Ex Vivo Human AAA Specimens (Aim 2A)

Other group

Description:

Tissue samples obtained from an existing tissue bank as well as discarded tissue obtained from participants in this study will be examined to assess the sensitivity and specificity of 64Cu-DOTA-ECL1i binding to ex vivo to human AAA specimens.

Treatment:

Other: Ex Vivo Human AAA Specimens (Aim 2A)

Radiotracer and CCR2 (Aim 2B)

Other group

Description:

Tissue samples obtained from an existing tissue bank as well as discarded tissue obtained from participants in this study will be examined to better understand the relationship between the levels of CCR2+ inflammatory cells and the inflammatory and clinical status of AAA, to gain insight into the importance of proinflammatory monocytes/macrophages in the development of AAA disease at the time of elective AAA repair.

Treatment:

Other: Relationship between radiotracer and CCR2 (Aim 2B)

AAA Group (Aim 3B-Reproducibility)

Experimental group

Description:

20 (10 men; 10 women) will receive a second PET/CT imaging study performed 10-14 days after the first PET/CT in order to determine the ability to reproduce the uptake results. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.

Treatment:

Diagnostic Test: AAA Group (Aim 3B-Reproducibility)