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. The study, conducted at Houston Methodist Research Institute under the direction of Dr. Alireza Faridar, represents a novel approach to treating Alzheimer's disease by targeting the immune dysregulation that contributes to 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.
| 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 |
Alzheimer's 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:
| Immune Abnormality | Evidence | Impact |
|---|---|---|
| Reduced Treg function | Decreased Treg numbers and suppressive capacity in AD patients[1] | Loss of immune regulation, increased inflammation |
| Elevated pro-inflammatory cytokines | Increased IL-1β, TNF-α, IL-6 in AD brains and CSF[2] | 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[3] | Potential autoimmune attack on neurons |
| Immunosenescence | Accelerated aging of immune system in AD[4] | Reduced immune function, chronic inflammation |
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.
In Alzheimer's disease, Tregs are compromised:
This loss of immune regulation contributes to the chronic neuroinflammation that drives disease progression.
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.
A fascinating phenomenon in immunology is that low-dose IL-2 preferentially expands Tregs relative to effector T cells. This occurs because:
This selective effect makes low-dose IL-2 an attractive therapeutic strategy for diseases where Treg deficiency plays a role, including Alzheimer's disease.
This is a randomized, double-blind, placebo-controlled trial - the gold standard for clinical research.
| 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:
The specific dose range is based on:
| 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 | 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 |
Safety assessments include:
The primary safety concern with IL-2 is capillary leak syndrome (vascular leak syndrome), characterized by:
Low-dose IL-2 minimizes this risk while maintaining Treg expansion.
Key immunologic endpoint:
| 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 |
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 |
|---|---|
| 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 |
Treg Expansion
Immune Balance Restoration
Neuroinflammation Reduction
Potential Disease Modification
Current Alzheimer's disease treatments:
This trial represents a different mechanism - targeting immune dysregulation rather than amyloid or tau directly.
| 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.
If successful, this trial could:
Alzheimer's disease affects over 6 million Americans:
If low-dose IL-2 is effective:
This trial represents the beginning of immune-targeted approaches:
The trial incorporates extensive biomarker collection to:
Larbi, A., et al. Dramatic decrease in circulating T cells in Alzheimer's disease. Mechanisms of Ageing and Development. 2009. ↩︎
Swardfager, W., et al. Meta-analysis of cytokines in Alzheimer's disease. Biological Psychiatry. 2018. ↩︎
Gate, D., et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature. 2020. ↩︎
Pehlivan, F.E., et al. Immunosenescence and neuroinflammation in Alzheimer's disease. Ageing Research Reviews. 2023. ↩︎