Interleukin-2 Phase 2 (NCT06096090) — Immunomodulation for AD

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Interleukin-2 Phase 2 (NCT06096090) — Immunomodulation for AD

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Interleukin-2 Phase 2 (NCT06096090) — Immunomodulation for Alzheimer's Disease

Executive Summary

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This Phase 2 clinical trial investigates the use of low-dose interleukin-2 (IL-2) immunotherapy in patients with mild to moderate [Alzheimer's disease](/diseases/alzheimers-disease). The study, conducted at Houston Methodist Research Institute under the direction of Dr. Alireza Faridar, represents a novel approach to treating [Alzheimer's disease](/diseases/alzheimers-disease) by targeting the immune dysregulation that contributes to [neuroinflammation](/mechanisms/neuroinflammation) and disease progression.

Unlike conventional approaches that target amyloid or tau pathology directly, this trial focuses on modulating the immune system by expanding and restoring functional regulatory T cells (Tregs). This immunomodulation strategy addresses a critical but underappreciated component of [Alzheimer's disease pathophysiology](/mechanisms/neuroinflammation).

Trial Overview

...

Interleukin-2 Phase 2 (NCT06096090) — Immunomodulation for Alzheimer's Disease

Executive Summary

Mermaid diagram (expand to render)

This Phase 2 clinical trial investigates the use of low-dose interleukin-2 (IL-2) immunotherapy in patients with mild to moderate [Alzheimer's disease](/diseases/alzheimers-disease). The study, conducted at Houston Methodist Research Institute under the direction of Dr. Alireza Faridar, represents a novel approach to treating [Alzheimer's disease](/diseases/alzheimers-disease) by targeting the immune dysregulation that contributes to [neuroinflammation](/mechanisms/neuroinflammation) and disease progression.

Unlike conventional approaches that target amyloid or tau pathology directly, this trial focuses on modulating the immune system by expanding and restoring functional regulatory T cells (Tregs). This immunomodulation strategy addresses a critical but underappreciated component of [Alzheimer's disease pathophysiology](/mechanisms/neuroinflammation).

Trial Overview

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT06096090 |
| Status | Recruiting |
| Phase | Phase 2 |
| Condition | Alzheimer's Disease |
| Intervention | Interleukin-2 (Aldesleukin) |
| Sponsor | The Methodist Hospital Research Institute |
| Lead Investigator | Alireza Faridar, MD, PhD (Assistant Professor) |
| Location | Houston Methodist Research Institute, Houston, Texas |
| Start Date | January 1, 2022 |
| Primary Completion | December 30, 2025 |
| Study Completion | December 30, 2025 |
| Estimated Enrollment | 40 patients |
| Study Duration | 6-month treatment period + follow-up |

Scientific Rationale

Immune Dysregulation in Alzheimer's Disease

[Alzheimer's disease](/diseases/alzheimers-disease) is increasingly recognized as a disease with significant immune system dysfunction. Research over the past two decades has revealed that the immune system plays a dual role in Alzheimer's disease:

Protective functions: Microglial cells clear amyloid, respond to pathogens, and maintain brain homeostasis

Pathogenic contributions: Chronic inflammation, impaired immune regulation, and autoimmune-like responses drive neurodegeneration

Key Immune Abnormalities in AD

| Immune Abnormality | Evidence | Impact |
|-------------------|----------|--------|
| Reduced Treg function | Decreased Treg numbers and suppressive capacity in AD patients[@larbi2009] | Loss of immune regulation, increased inflammation |
| Elevated pro-inflammatory cytokines | Increased IL-1β, TNF-α, IL-6 in AD brains and CSF[@swardfager2018] | Neurotoxicity, synaptic dysfunction |
| Microglial dysregulation | Altered microglial morphology and function in AD brains | Impaired amyloid clearance, chronic inflammation |
| CD8+ T cell infiltration | Clonally expanded CD8+ T cells found in AD brains[@gate2020] | Potential autoimmune attack on neurons |
| Immunosenescence | Accelerated aging of immune system in AD[@pehlivan2023] | Reduced immune function, chronic inflammation |

Regulatory T Cells: The Immune "Brakes"

Regulatory T cells (Tregs) are a specialized subset of T cells that maintain immune homeostasis and prevent excessive inflammatory responses. They function as the "brakes" of the immune system, suppressing the activity of effector T cells, microglia, and other immune cells.

Treg Biology

Development: Tregs develop in the thymus (tTregs) or peripheral tissues (pTregs)

Surface markers: CD4+, CD25+, FOXP3+ (key transcription factor)

Mechanisms of suppression:

Cell-contact dependent inhibition
Cytokine secretion (IL-10, TGF-β, IL-35)
Metabolic disruption of effector cells
IL-2 consumption (competitive IL-2 deprivation)

Tregs in Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), Tregs are compromised:

Reduced numbers: AD patients show decreased circulating Tregs compared to age-matched controls
Impaired function: Tregs from AD patients have reduced suppressive capacity
FOXP3 dysregulation: Altered FOXP3 expression and methylation patterns
Pro-inflammatory shift: Some Tregs convert to pro-inflammatory Th17 cells

This loss of immune regulation contributes to the chronic neuroinflammation that drives [disease progression](/mechanisms/neuroinflammation).

IL-2: The Treg Growth Factor

Interleukin-2 (IL-2) is a critical cytokine for Treg survival, proliferation, and function. Discovered in 1976, IL-2 was originally characterized as a T cell growth factor but is now understood to have complex, context-dependent effects on the immune system.

IL-2 Signaling

Receptor binding: IL-2 binds to the IL-2 receptor (CD25/CD122/CD132 trimeric complex)

Signal transduction: JAK-STAT, PI3K-AKT, and MAPK pathways

Cellular outcomes:

T effector cells: Proliferation, activation
Tregs: Survival, expansion, enhanced suppressive function
NK cells: Enhanced cytotoxicity

The Low-Dose IL-2 Paradox

A fascinating phenomenon in immunology is that low-dose IL-2 preferentially expands Tregs relative to effector T cells. This occurs because:

Tregs constitutively express high levels of CD25 (IL-2 receptor alpha chain)
This gives Tregs a competitive advantage for IL-2 binding at low concentrations
Effector T cells require higher IL-2 concentrations for activation
The result: selective Treg expansion with minimal effector cell activation

This selective effect makes low-dose IL-2 an attractive therapeutic strategy for diseases where Treg deficiency plays a role, including [Alzheimer's disease](/diseases/alzheimers-disease).

Study Design

Trial Type

This is a randomized, double-blind, placebo-controlled trial - the gold standard for clinical research.

Randomization

Ratio: 1:1 (active:placebo)
Stratification: By disease severity (MMSE score)
Block size: Variable (4-6)

Treatment Arms

| Arm | Treatment | Dose | Schedule |
|-----|-----------|------|----------|
| Active | IL-2 (Aldesleukin) | Low dose | Every 2 weeks OR Every 4 weeks |
| Placebo | Matching saline | N/A | Every 2 weeks OR Every 4 weeks |

The study investigates two different dosing schedules to optimize the Treg expansion effect:

Every 2 weeks: More frequent but lower total exposure
Every 4 weeks: Less frequent with potential for higher individual doses

Dosing Rationale

The specific dose range is based on:

Previous studies in other autoimmune conditions showing Treg selectivity
Phase 1 safety data in elderly populations
Target blood levels for optimal Treg expansion
Balance between efficacy and safety

Eligibility Criteria

Inclusion Requirements

| Criterion | Requirement |
|-----------|-------------|
| Age | 50-86 years |
| Diagnosis | Probable Alzheimer's disease per NIA-AA criteria |
| Cognitive status | MMSE 12-26 (mild to moderate impairment) |
| Biomarker | Positive amyloid PET or CSF biomarkers |
| Laboratory | Normal bilirubin, liver enzymes, albumin, creatinine, blood counts, INR |
| Medications | Stable doses of AD medications for ≥4 weeks |
| Capacity | Able to provide informed consent (patient or surrogate) |

Exclusion Criteria

| Exclusion | Reason |
|-----------|--------|
| Active infections | IL-2 can exacerbate immune responses |
| Severe cardiac dysfunction | IL-2 can cause fluid retention, hypotension |
| Hypersensitivity to IL-2 | Safety concern |
| Other primary degenerative dementias | Mixed pathology confounders |
| Active major depression, schizophrenia, bipolar | Psychiatric comorbidity |
| Recent cancer history (≤5 years) | Immunosuppression concerns |
| Contraindications to lumbar puncture | CSF sampling required |
| Immunosuppressive therapy | Interaction with IL-2 effect |
| Prior IL-2 therapy | Prior exposure confounders |
| Active autoimmune disease | Autoimmune confounds |

Key Assessments

Screening Evaluations

Medical and neurological history
Physical examination
Cognitive testing (MMSE, CDR, ADAS-Cog)
Laboratory tests (CBC, CMP, coagulation)
Amyloid PET or CSF biomarkers
MRI brain (within 6 months)
ECG
Lumbar puncture (for biomarker collection)

Treatment Period Evaluations

Vital signs and physical exams at each visit
Laboratory monitoring at regular intervals
Cognitive testing at baseline, 3 months, 6 months
CSF sampling at baseline and 6 months
Adverse event monitoring

Endpoints

Primary Outcomes

Safety and Tolerability (6 months)

Safety assessments include:

Adverse events (AEs) - incidence, severity, relationship
Serious adverse events (SAEs) - monitoring for significant complications
Laboratory abnormalities - hematology, chemistry
Vital sign changes - blood pressure, heart rate, temperature
ECG changes - cardiac safety monitoring

The primary safety concern with IL-2 is capillary leak syndrome (vascular leak syndrome), characterized by:

Hypotension
Edema
Weight gain
Reduced organ perfusion

Low-dose IL-2 minimizes this risk while maintaining Treg expansion.

Treg Percentage Change

Key immunologic endpoint:

Measurement: Percentage of Tregs (CD4+CD25+FOXP3+) out of total CD4+ T cells
Timepoints: Baseline, 2 weeks, 6 weeks, 3 months, 6 months
Hypothesis: Low-dose IL-2 will increase Treg percentage by ≥50% from baseline

Secondary Outcomes

| Endpoint | Measurement | Timepoints |
|----------|-------------|------------|
| Cognitive function | MMSE, ADAS-Cog13, CDR | Baseline, 3 months, 6 months |
| Functional status | ADCS-ADL | Baseline, 3 months, 6 months |
| Neuropsychiatric symptoms | NPI | Baseline, 3 months, 6 months |
| Brain volumetry | MRI | Baseline, 6 months |
| CSF biomarkers | Aβ42/40, t-tau, p-tau181 | Baseline, 6 months |
| Inflammatory markers | Cytokines in plasma/CSF | Baseline, 6 months |
| Quality of life | QoL-AD | Baseline, 6 months |

Exploratory Endpoints

Treg functional assays (suppression capacity)
Microbiome analysis (gut-immune-brain axis)
Genetic predictors of response (IL2RA polymorphisms)
Machine learning models for response prediction

Immunologic Monitoring

Treg Assessment Flow

Baseline → Week 2 → Week 6 → Month 3 → Month 6
↓ ↓ ↓ ↓ ↓
Blood draws for flow cytometry analysis
↓
↓
Measure: CD4+CD25+FOXP3+ percentage and absolute count
Treg suppressive function
Serum IL-2 and soluble IL-2R

Biomarker Rationale

| Biomarker | Rationale |
|-----------|-----------|
| Treg percentage | Direct measure of drug effect on target |
| Treg function | Assesses whether expanded Tregs are functional |
| Inflammatory cytokines | IL-6, TNF-α, IL-1β - tracks neuroinflammation |
| Amyloid/tau biomarkers | Disease progression markers |
| Brain volume | Structural change measure |

Mechanism of Action

How Low-Dose IL-2 May Benefit Alzheimer's Disease

Treg Expansion

IL-2 stimulates proliferation of existing Tregs
Increases CD25 expression (positive feedback)
Promotes Treg survival and longevity

Immune Balance Restoration

Tregs suppress effector T cells and microglia
Reduces pro-inflammatory cytokine production
Shifts microglial phenotype from M1 (pro-inflammatory) to M2 (protective)

Neuroinflammation Reduction

Decreased IL-1β, TNF-α, IL-6 in the brain
Reduced microglial activation
Decreased T cell infiltration into CNS

Potential Disease Modification

By reducing chronic inflammation, may slow neurodegenerative processes
May preserve synaptic function and neuronal survival
May improve cognitive outcomes

Preclinical Evidence

Animal Models

5xFAD mice: Low-dose IL-2 reduced microglial activation and improved cognition
APP/PS1 mice: IL-2 treatment decreased amyloid plaques via Treg-mediated mechanisms
Aging mice: IL-2 restored Treg numbers and improved hippocampal function

Human Studies

Autoimmune conditions: Low-dose IL-2 safely expands Tregs in SLE, RA, type 1 diabetes
Cancer patients: High-dose IL-2 used for melanoma and renal cell carcinoma (different safety profile)
Healthy elderly: IL-2 improves Treg function and immune parameters

Clinical Significance

Addressing an Unmet Need

Current [Alzheimer's disease](/diseases/alzheimers-disease) treatments:

Amyloid-targeting antibodies (lecanemab, donanemab): Important but only modestly effective
Symptomatic medications (donepezil, memantine): Limited benefit
Immunomodulatory approaches: Underdeveloped

This trial represents a different mechanism - targeting immune dysregulation rather than amyloid or tau directly.

Advantages of the Approach

Disease mechanism targeting: Addresses neuroinflammation, a core pathological feature

Combination potential: Could be combined with anti-amyloid therapies

Well-characterized safety: IL-2 has been used for decades in other conditions

Orphan mechanism: Targets the Treg deficiency in AD

Biomarker-driven: Can measure target engagement directly

Challenges and Limitations

CNS penetration: IL-2 is a large molecule; CNS effects may be indirect

Treg specificity: Some effector T cell activation may occur

Dosing optimization: Optimal dose and schedule not established for AD

Biomarker validation: CSF vs. blood Tregs correlation unclear

Long-term effects: 6-month treatment may be insufficient

Comparison with Other Immunotherapy Approaches

| Approach | Target | Mechanism | Status |
|----------|--------|-----------|--------|
| Lecanemab | Amyloid plaques | Antibody-mediated clearance | Approved |
| Donanemab | Amyloid plaques | Antibody-mediated clearance | Approved |
| Aducanumab | Amyloid plaques | Antibody-mediated clearance | Withdrawn |
| Tilavonemab | Tau aggregates | Antibody-mediated clearance | Phase 2 |
| Semorinemab | Tau | Antibody-mediated | Phase 2 |
| AL-002 | TREM2 | Microglial activation | Phase 1 |
| Low-dose IL-2 (this trial) | Immune dysregulation | Treg expansion | Phase 2 |

This trial is unique in targeting immune regulation rather than protein aggregation.

Regulatory Considerations

Current Status

IND: Active
Orphan drug: Not specifically for AD (immunomodulators have precedent)
Fast track: Not granted (not a high-priority pathway)

Future Directions

If successful, this trial could:

Establish proof-of-concept for Treg-targeted therapy in AD

Identify biomarkers predicting response

Guide combination trials with anti-amyloid agents

Support expanded Phase 3 development

Patient Perspective

Burden of Alzheimer's Disease

[Alzheimer's disease](/diseases/alzheimers-disease) affects over 6 million Americans:

Cognitive decline: Memory loss, disorientation, language difficulties
Functional impairment: Loss of independence, need for caregiving
Behavioral changes: Depression, agitation, sleep disturbances
Family impact: Caregiver burden, financial costs, emotional distress

Current Treatment Limitations

Symptomatic therapies: Provide modest, temporary benefit
Disease-modifying therapies: Limited efficacy, significant risks (ARIA)
Immunotherapy gap: No immunomodulatory approaches available

Potential Benefits of This Approach

If low-dose IL-2 is effective:

Reduced neuroinflammation
Slowed cognitive decline
Maintained independence longer
Improved quality of life
Potential for combination with other therapies

Risks

Flu-like symptoms (common with IL-2)
Capillary leak syndrome (rare at low dose)
Injection site reactions
Potential for infection (immunosuppression)
Unknown long-term effects

Future Directions

Next-Generation Immunomodulation

This trial represents the beginning of immune-targeted approaches:

Combination trials: IL-2 + anti-amyloid antibodies

Novel IL-2 formulations: PEGylated IL-2 for improved PK

Alternative targets: TREM2 agonists, CD22 inhibitors

Cell therapy: Ex vivo expanded Tregs

Microbiome modulation: Gut-immune-brain axis approaches

Biomarker Development

The trial incorporates extensive biomarker collection to:

Validate target engagement (Tregs in blood/CSF)
Identify predictors of response
Enable patient selection for Phase 3
Support regulatory approval

Disease and Mechanism Pages

[Alzheimer's Disease](/diseases/alzheimers-disease) — Overview of AD pathology and treatments
[Neuroinflammation](/mechanisms/neuroinflammation) — Mechanism of neuroinflammation in neurodegeneration
[Tau Protein](/proteins/tau) — Target of other immunotherapies
[Amyloid Beta](/proteins/amyloid-beta) — Amyloid hypothesis and therapies

Therapeutic Approaches

[Immunotherapy Approaches for AD](/therapeutics/immunotherapy-alzheimers) — Overview of immunotherapy strategies
[Anti-Amyloid Immunotherapy](/mechanisms/anti-amyloid-immunotherapy) — Monoclonal antibody approaches

[Lecanemab (NCT01767311)](https://clinicaltrials.gov/study/NCT01767311) — Anti-amyloid antibody
[Donanemab (NCT04468657)](https://clinicaltrials.gov/study/NCT04468657) — Anti-amyloid antibody
[Tilavonemab (NCT03580956)](https://clinicaltrials.gov/study/NCT03580956) — Anti-tau antibody

References

[Faridar et al., Low-dose interleukin-2 for Alzheimer's disease: rationale and trial design (2022)](https://doi.org/10.14283/jpad.2022.45)

[Yu et al., Regulatory T cells in Alzheimer's disease: friend or foe? (2020)](https://doi.org/10.1186/s12974-020-01942-3)

[Larbi et al., Dramatic decrease in circulating T cells in Alzheimer's disease (2009)](https://doi.org/10.1016/j.mad.2009.09.005)

[Swardfager et al., Meta-analysis of cytokines in Alzheimer's disease (2018)](https://doi.org/10.1016/j.biopsych.2018.06.015)

[Gate et al., Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease (2020)](https://doi.org/10.1038/s41586-020-2246-5)

[Pehlivan et al., Immunosenescence and neuroinflammation in Alzheimer's disease (2023)](https://doi.org/10.1016/j.arr.2023.101857)

[NCT06096090 - ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT06096090)

[Houston Methodist Research Institute](https://www.houstonmethodist.org/research/)

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📊 Evidence Profile Foundational

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Outgoing

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0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Interleukin-2 Phase 2 (NCT06096090) — Immunomodulation for AD

Interleukin-2 Phase 2 (NCT06096090) — Immunomodulation for Alzheimer's Disease

Executive Summary

Trial Overview

Interleukin-2 Phase 2 (NCT06096090) — Immunomodulation for Alzheimer's Disease

Executive Summary

Trial Overview

Scientific Rationale

Immune Dysregulation in Alzheimer's Disease

Key Immune Abnormalities in AD

Regulatory T Cells: The Immune "Brakes"

Treg Biology

Tregs in Alzheimer's Disease

IL-2: The Treg Growth Factor

IL-2 Signaling

The Low-Dose IL-2 Paradox

Study Design

Trial Type

Randomization

Treatment Arms

Dosing Rationale

Eligibility Criteria

Inclusion Requirements

Exclusion Criteria

Key Assessments

Screening Evaluations

Treatment Period Evaluations

Endpoints

Primary Outcomes

Safety and Tolerability (6 months)

Treg Percentage Change

Secondary Outcomes

Exploratory Endpoints

Immunologic Monitoring

Treg Assessment Flow

Biomarker Rationale

Mechanism of Action

How Low-Dose IL-2 May Benefit Alzheimer's Disease

Preclinical Evidence

Animal Models

Human Studies

Clinical Significance

Addressing an Unmet Need

Advantages of the Approach

Challenges and Limitations

Comparison with Other Immunotherapy Approaches

Regulatory Considerations

Current Status

Future Directions

Patient Perspective

Burden of Alzheimer's Disease

Current Treatment Limitations

Potential Benefits of This Approach

Risks

Future Directions

Next-Generation Immunomodulation

Biomarker Development

Related Pages

Disease and Mechanism Pages

Therapeutic Approaches

Related Clinical Trials

References

💬 Discussion