ClinicalTrials.gov Identifier: NCT06384378
| Attribute | Details |
|---|---|
| Phase | Phase 2 |
| Status | Recruiting |
| Sponsor | The Methodist Hospital Research Institute |
| Intervention | Low-dose IL-2 (interleukin-2) immunotherapy |
| Indication | Alzheimer's Disease |
| Study Design | Randomized, quadruple-blind, parallel assignment |
| Enrollment | 40 participants |
| Location | Houston Methodist Research Institute, Houston, Texas |
Central and Peripheral Immune Cross-talk in Alzheimer's Disease and Their Modulation by a Novel Immunotherapy
This trial investigates low-dose interleukin-2 (IL-2) immunotherapy as a novel approach to modulate neuroinflammation in Alzheimer's disease. The rationale stems from growing recognition that immune dysregulation plays a central role in AD pathogenesis.
Low-dose IL-2 therapy is based on the understanding that:
Regulatory T-cell (Treg) Enhancement — Low-dose IL-2 preferentially expands regulatory T cells, which are essential for maintaining immune homeostasis[1]. In Alzheimer's disease, Tregs are often numerically and functionally deficient, contributing to unchecked neuroinflammation[2].
Cytokine Balance Restoration — IL-2 helps restore the balance between pro-inflammatory and anti-inflammatory cytokines. The neuroinflammation pathway in AD is characterized by elevated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) relative to anti-inflammatory signals.
Microglial Modulation — Microglia are the resident immune cells of the brain and play a dual role in neurodegeneration[3]. Low-dose IL-2 may shift microglia from a pro-inflammatory (M1) to a neuroprotective (M2-like) phenotype.
A unique feature of this trial is the use of 11C-ER176, a PET tracer that binds to the 18 kDa translocator protein (TSPO), formerly known as the peripheral benzodiazepine receptor. TSPO is expressed primarily by activated microglia and astrocytes, making it a validated biomarker of brain inflammation[4].
| Arm | Intervention | Dosing Frequency |
|---|---|---|
| Active Comparator 1 | IL-2 | Every 2 weeks |
| Active Comparator 2 | IL-2 | Every 4 weeks |
| Placebo Control | Placebo | Matching schedule |
The study employs quadruple blinding, meaning that participants, care providers, investigators, and outcome assessors are all blinded to treatment assignment. This minimizes bias in both subjective and objective outcome measures.
The combination of peripheral and central biomarkers with direct imaging of neuroinflammation provides a comprehensive assessment of IL-2's immunomodulatory effects. This is particularly important given the growing recognition of the gut-brain axis and central-peripheral immune cross-talk in neurodegeneration.
This trial represents an emerging therapeutic approach that draws on experience from:
The translation to Alzheimer's disease follows the immunomodulation rather than immunosuppression paradigm, seeking to restore rather than suppress immune function.
| Trial | Target | Phase | Status |
|-------|--------|-------||
| NCT06384378 (IL-2) | Treg expansion, cytokine modulation | Phase 2 | Recruiting |
| NCT01796964 (CNR1) | Cannabinoid receptor | Phase 2 | Completed |
| NCT03478514 (JNJ-54175446) | P2X7 receptor | Phase 2 | Completed |
| NCT05318998 (AL002) | TREM2 agonist | Phase 2 | Active |
The sponsor, Houston Methodist Research Institute, is a leading academic medical center with expertise in Alzheimer's disease clinical trials and neuroimaging.
Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nature Reviews Immunology. 2015. ↩︎
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nature Reviews Immunology. 2010. ↩︎
Heneka MT, et al. Neuroinflammation in Alzheimer's disease. The Lancet Neurology. 2015. ↩︎
Cosenza-Nashat M, et al. Alterations in the peripheral benzodiazepine receptor in neurodegenerative diseases. Journal of Neuropathology & Experimental Neurology. 2011. ↩︎
Rosenzwajg M, et al. Low-dose IL-2 in patients with active systemic lupus erythematosus: a phase I/IIa clinical trial. JCI Insight. 2019. ↩︎