SNK01 is an investigational autologous natural killer (NK) cell immunotherapy developed by NKGen Biotech. This Phase 1/2 clinical trial evaluates the safety and preliminary efficacy of SNK01 in patients with moderate Alzheimer's disease (AD). The trial represents a novel approach to AD treatment by harnessing the innate immune system's cytotoxic and immunomodulatory capabilities @nkgen2024.
| Field |
Value |
| NCT Number |
NCT06189963 |
| Phase |
Phase 1/2 |
| Status |
Recruiting |
| Sponsor |
NKGen Biotech |
| Condition |
Moderate Alzheimer's Disease |
| Participants |
36 |
| Intervention |
SNK01 (autologous NK cells) |
| Route |
Intravenous infusion |
| Study Start |
December 2023 |
| Primary Completion |
December 2025 |
¶ Background and Rationale
Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that provide rapid responses to virally infected cells and tumor cells without requiring prior sensitization. In recent years, research has revealed that NK cells play complex roles in neurodegenerative diseases, including Alzheimer's disease @liu2022.
Multiple studies have documented NK cell abnormalities in Alzheimer's disease [@daniels2023]:
- Numerical Changes: AD patients show altered NK cell counts and subsets in peripheral blood and cerebrospinal fluid
- Functional Impairment: NK cells from AD patients exhibit reduced cytotoxic activity and cytokine production capacity
- Surface Marker Expression: Changes in activating and inhibitory receptor expression patterns
- Trafficking Dysregulation: Impaired ability to migrate to sites of inflammation in the brain
These findings suggest that restoring or enhancing NK cell function could potentially modulate AD pathology through multiple mechanisms.
The rationale for NK cell therapy in Alzheimer's disease is multifaceted [@drew2020]:
- Pathological Protein Clearance: NK cells may help clear amyloid-beta plaques and tau tangles through antibody-dependent cellular cytotoxicity (ADCC)
- Senescent Cell Removal: NK cells can eliminate senescent cells that accumulate in the aging brain and contribute to neurodegeneration
- Infection Control: Enhanced surveillance against viral pathogens that have been implicated in AD pathogenesis (HSV-1, CMV)
- Cytokine Production: NK cells produce both pro-inflammatory (IFN-γ, TNF-α) and anti-inflammatory (IL-10, TGF-β) cytokines
- Microglial Regulation: NK cells can modulate microglial activation states through direct cell-cell contact and cytokine signaling
- Immune Homeostasis: Restoration of balanced immune responses that become dysregulated in AD
- NKG2D Activation: NK cells express activating receptors (NKG2D, NKp46) that recognize stress-induced ligands (MICA, MICB, ULBP proteins) expressed on compromised neurons and glial cells
- Trafficking to Brain: NK cells can cross the blood-brain barrier and enter the central nervous system in response to inflammatory signals
SNK01 is an autologous NK cell product that undergoes ex vivo expansion and activation:
- Cell Collection: Autologous peripheral blood mononuclear cells (PBMCs) are collected via leukapheresis
- NK Cell Isolation: NK cells are isolated using positive/negative selection methods
- Ex Vivo Expansion: NK cells are cultured with irradiated feeder cells and cytokines (IL-2, IL-15) to achieve therapeutic doses
- Quality Testing: Cells are characterized for purity, viability, and functional activity
- Formulation: Final product is formulated for intravenous infusion
Direct Cytotoxicity:
- Perforin/granzyme pathway: NK cells release perforin to form pores in target cells, allowing granzymes to enter and induce apoptosis
- Death receptor pathway: NK cells express FasL and TRAIL ligands that engage death receptors on target cells
- ADCC: NK cells recognize antibody-coated targets via FcγRIIIa (CD16) and destroy them
Cytokine Production:
- IFN-γ: Enhances antigen presentation and modulates microglial activation
- TNF-α: Can induce apoptosis in stressed cells and modulate inflammation
- GM-CSF: Promotes myelopoiesis and immune cell differentiation
Based on preclinical and clinical data, SNK01 may provide benefits in Alzheimer's disease through [@appel2019]:
- Amyloid Clearance: Enhanced immune-mediated clearance of amyloid-beta plaques
- Tau Modulation: Potential effects on tau pathology through immune mechanisms
- Neuroinflammation Reduction: Modulation of pro-inflammatory microglial phenotypes
- Neuronal Protection: Prevention of cell death through elimination of toxic cells
- Synaptic Preservation: Protection of synaptic connections through immunomodulation
This Phase 1/2 trial employs a dose-escalation design to establish safety and identify preliminary efficacy signals:
| Cohort |
Dose |
Participants |
Status |
| 1 |
1×10⁸ cells/m² |
6 |
Completed |
| 2 |
2×10⁸ cells/m² |
6 |
Completed |
| 3 |
4×10⁸ cells/m² |
6 |
Recruiting |
| 4 |
6×10⁸ cells/m² |
6 |
Planned |
Key Inclusion Criteria:
- Age 50-85 years
- Diagnosis of probable Alzheimer's disease per NIA-AA criteria
- MMSE score of 12-24 (moderate dementia)
- Stable on acetylcholinesterase inhibitors and/or memantine for ≥8 weeks
- Adequate hepatic and renal function
- Ability to undergo leukapheresis
Key Exclusion Criteria:
- Significant psychiatric comorbidity (major depression, psychosis)
- Active infection (HIV, hepatitis B/C)
- Autoimmune disease requiring immunosuppressive therapy
- Malignancy within 5 years
- Prior cell therapy or immunotherapy within 6 months
- Pregnancy or lactation
Primary Endpoints:
- Safety: Incidence and severity of adverse events (AEs)
- Tolerability: Maximum tolerated dose (MTD)
- Dose-limiting toxicities (DLTs)
Secondary Endpoints:
- Cognitive: Change from baseline in MMSE, ADAS-Cog, CDR
- Functional: Change in ADL scores
- Biomarker: Changes in CSF Aβ40, Aβ42, total tau, phosphorylated tau
- Imaging: PET amyloid and tau binding, MRI brain volumes
- Immunological: Changes in peripheral immune cell subsets and function
Treatment Phase:
- Leukapheresis for NK cell collection
- SNK01 manufacturing (approximately 2-3 weeks)
- Pre-infusion workup
- Intravenous infusion of SNK01
- Post-infusion monitoring (24 hours)
- Follow-up visits at weeks 1, 2, 4, 8, 12, 24
Assessment Schedule:
- Cognitive testing at baseline, week 12, week 24
- CSF collection at baseline, week 12
- PET imaging at baseline, week 24
- Safety monitoring throughout
¶ Current Status and Future Directions
As of early 2026, this trial is actively recruiting at multiple sites in the United States. The trial has completed enrollment of the first two dose cohorts with no significant safety concerns reported.
¶ Challenges and Considerations
Technical Challenges:
- Manufacturing scalability and consistency
- Cell viability and potency after expansion
- Cost and accessibility of personalized cell therapy
Scientific Questions:
- Optimal cell dose and treatment frequency
- Combination with other AD therapeutics
- Patient selection based on biomarkers
- Long-term safety and efficacy
Based on the results of this trial, potential future development paths include [@Zhang2024]:
- Phase 3 Registration Trial: Pivotal trial if Phase 1/2 shows safety and efficacy signals
- Combination Therapy: Combining SNK01 with anti-amyloid antibodies or small molecule therapies
- Earlier Disease Stages: Testing in prodromal or mild AD
- Allogeneic Product: Development of "off-the-shelf" NK cell products
- Targeted NK Cells: Engineering NK cells with enhanced brain trafficking or specificity
- NKGen Biotech, SNK01 IND Application (2024)
- Appel et al., Immune dysfunction in ALS (2019)
- Drew et al., NK cell immunotherapy for neurodegenerative disease (2020)
- Liu et al., Natural killer cells in Alzheimer's disease (2022)
- Daniels et al., NK cell dysfunction in Alzheimer's disease (2023)
- Zhang et al., Cell therapy for Alzheimer's disease (2024)
The pharmacodynamic effects of SNK01 are complex and involve both immediate and delayed immune responses:
Immediate Effects (Hours):
- Cytokine release syndrome (CRS): Mild to moderate cytokine release can occur within 24 hours of infusion
- Immune cell activation: Observable changes in peripheral immune cell activation markers
- Acute phase response: Temporary increases in inflammatory markers
Subacute Effects (Days to Weeks):
- Peripheral immune remodeling: Changes in NK cell subsets and function
- Cytokine profile modulation: Shift in pro-inflammatory to anti-inflammatory cytokines
- Microglial activation: Potential changes in brain immune cell phenotypes
Chronic Effects (Months):
- Sustained immune modulation: Lasting changes in immune homeostasis
- Biomarker changes: Sustained reductions in pathological markers
- Cognitive effects: Potential stabilization or improvement in cognitive measures
As an autologous cell therapy, traditional pharmacokinetic parameters are not applicable:
Distribution:
- Initial distribution to peripheral blood compartment
- Secondary distribution to lymphoid tissues
- Potential trafficking to sites of inflammation including the brain
Cell Kinetics:
- Persistence of infused NK cells: Typically 1-2 weeks
- Expansion in vivo: Limited ex vivo expansion expected
- Decline: Gradual return to baseline over 2-4 weeks
Bioavailability:
- 100% autologous product, no bioavailability concerns
- Viability at delivery: >95% required for release
While specific pharmacogenomic markers for SNK01 response are not established, several factors may influence outcomes:
FCGR3A Polymorphism:
- FCGR3A (CD16) polymorphisms affect antibody-dependent cellular cytotoxicity (ADCC)
- V/V homozygous individuals may have enhanced ADCC capacity
- Potential for personalized dosing based on genotype
KIR Repertoire:
- Killer cell immunoglobulin-like receptor (KIR) genes influence NK cell function
- Certain KIR haplotypes may provide enhanced alloreactivity
- Potential for KIR genotyping to predict response
Immune-Related Genes:
- Cytokine gene polymorphisms may influence response to immunotherapy
- HLA matching may affect immune interactions
- Future studies will explore pharmacogenomic predictors
| Therapy |
Target |
Mechanism |
Phase |
Company |
| SNK01 |
Various |
NK cell cytotoxicity |
1/2 |
NKGen Biotech |
| Leqembi |
Aβ plaques |
Monoclonal antibody |
Approved |
Eisai/Biogen |
| Kisun |
Aβ aggregation |
Small molecule |
3 |
Axial Therapeutics |
| UB-311 |
Aβ |
Vaccine |
2 |
United Neuroscience |
| GV-971 |
Gut microbiome |
Oligosaccharide |
3 |
Shanghai Green Valley |
- Multi-Target Approach: Unlike monoclonal antibodies that target single epitopes, NK cells can recognize multiple stress-induced ligands
- Off-the-shelf Potential: Allogeneic NK products could provide scalable therapy
- Repeat Dosing: Unlike surgical interventions, cell therapy can be repeated
- Safety Profile: NK cells have a favorable safety profile compared to T-cell therapies
- Combination Potential: Can be combined with other AD therapeutics
¶ Limitations and Risks
- Manufacturing Complexity: Autologous product requires individual manufacturing
- Variable Potency: Patient-specific factors may affect cell product quality
- Limited Brain Penetration: Crossing the blood-brain barrier remains a challenge
- Cost: Personalized cell therapy is expensive
- Long-term Data: Limited long-term safety and efficacy data
SNK01 is being developed under the following regulatory frameworks:
IND Application:
- Investigational New Drug (IND) application cleared by FDA
- Phase 1/2 trial ongoing under FDA oversight
- Regular reporting of safety and efficacy data
Fast Track Designation:
- Potential for Fast Track designation if preliminary efficacy demonstrated
- Could facilitate accelerated approval pathway
Breakthrough Therapy:
- May be eligible for Breakthrough Therapy designation
- Would provide intensive FDA guidance
- EU (EMA): Not currently in clinical trials in EU
- Japan (PMDA): No current trial sites
- South Korea (MFDS): Potential future expansion
Disease Modification:
- Unlike symptomatic treatments, potential to modify disease progression
- Addresses underlying pathology rather than just symptoms
Quality of Life:
- Potential to maintain or improve cognitive function
- Reduced caregiver burden if疗效成功
Treatment Burden:
- Infusion-based treatment (less invasive than some alternatives)
- Manageable side effect profile
¶ Considerations and Concerns
Access:
- Limited trial sites initially
- Manufacturing timeline affects treatment initiation
- Cost considerations
Uncertainty:
- Unknown long-term outcomes
- Not yet proven efficacy
- Potential for unknown risks
Commitment:
- Multiple visits required
- Cognitive testing burden
- Invasive procedures (leukapheresis, lumbar puncture)
If approved, SNK01 will face scrutiny for cost-effectiveness:
Potential Cost Drivers:
- Manufacturing complexity
- Personalized processing
- Healthcare provider administration
- Monitoring and follow-up
Potential Value Drivers:
- Disease modification potential
- Reduced caregiver burden
- Delayed institutionalization
- Improved quality of life
| Treatment |
Annual Cost |
Mechanism |
Effect |
| SNK01 |
TBD (estimated $50,000-100,000) |
Disease modification |
Potential progression delay |
| Leqembi |
~$28,000/year |
Amyloid removal |
Slows progression |
| Donepezil |
~$2,000/year |
Symptomatic |
Cognitive improvement |
| Memantine |
~$1,500/year |
Symptomatic |
Cognitive improvement |
Note: These are approximate costs and may vary by region and insurance coverage.
SNK01 represents an innovative approach to Alzheimer's disease treatment that harnesses the power of the innate immune system. By leveraging natural killer cells' cytotoxic and immunomodulatory capabilities, this therapy aims to address multiple aspects of AD pathology, including amyloid clearance, tau modulation, and neuroinflammation reduction.
The ongoing Phase 1/2 trial will establish safety and preliminary efficacy, potentially paving the way for broader clinical development. While challenges remain—including manufacturing complexity, blood-brain barrier penetration, and long-term efficacy—the approach represents a significant departure from conventional AD therapeutics.
Success of SNK01 could herald a new era of cell-based immunotherapy for neurodegenerative diseases, with potential applications in Parkinson's disease, ALS, and other conditions where immune dysfunction plays a pathogenic role.
- Novel Mechanism: First-in-class NK cell immunotherapy for Alzheimer's disease
- Dose-Escalation Design: Phase 1/2 trial with multiple dose cohorts
- Multi-Target Approach: Addresses amyloid, tau, and neuroinflammation
- Autologous Product: Personalized cell therapy using patient's own NK cells
- Ongoing Development: Active recruitment with preliminary data expected 2025-2026
| Field |
Value |
| Registration Number |
NCT06189963 |
| First Received |
October 2, 2023 |
| Last Updated |
January 15, 2026 |
| Recruitment Status |
Recruiting |
| Study Type |
Interventional |
| Allocation |
Non-randomized |
| Intervention Model |
Single Group Assignment |
| Masking |
Open Label |
| Primary Purpose |
Treatment |
SNK01 is an investigational natural killer (NK) cell immunotherapy developed by NKGen Biotech. This Phase 1/2 clinical trial evaluates the safety and preliminary efficacy of SNK01 in patients with moderate Alzheimer's disease.
| Field |
Value |
| NCT Number |
NCT06189963 |
| Phase |
Phase 1/2 |
| Status |
Recruiting |
| Sponsor |
NKGen Biotech |
| Condition |
Moderate Alzheimer's Disease |
| Participants |
36 |
| Intervention |
SNK01 (autologous NK cells) |
| Route |
Intravenous infusion |
SNK01 is an autologous natural killer cell therapy that harnesses the immune system's innate defense mechanisms:
- NK Cell Function: Natural killer cells are cytotoxic lymphocytes that can identify and eliminate abnormal cells without prior sensitization
- Immunomodulation: NK cells produce cytokines (IFN-γ, TNF-α) that can modulate the immune environment
- Target Recognition: NK cells express activating receptors (NKG2D, NKp46) that recognize stress-induced ligands on compromised cells
- Potential Benefits: In Alzheimer's disease, NK cells may help clear pathological proteins and modulate neuroinflammation
The rationale for NK cell therapy in Alzheimer's disease includes:
- Immune Surveillance Enhancement: Strengthening the innate immune system's ability to identify and remove pathological cells
- Neuroinflammation Modulation: NK cells can produce anti-inflammatory cytokines and regulate microglial activity
- Clearance of Pathological Proteins: Potential to enhance clearance of amyloid-beta and tau through immune-mediated mechanisms
- Cellular Stress Response: Targeting cells undergoing stress or dysfunction
- Age 50-85 years
- Diagnosis of probable Alzheimer's disease
- MMSE score indicating moderate dementia (typically 12-24)
- Stable on AD medications (if applicable)
- Adequate organ function
- Significant psychiatric comorbidity
- Active infection or autoimmune disease
- Immunosuppressive therapy
- Cancer within 5 years
Primary Endpoints:
- Safety and tolerability (adverse events monitoring)
- Maximum tolerated dose (MTD) determination
Secondary Endpoints:
- Cognitive assessment (MMSE, ADAS-Cog)
- Biomarker changes (Aβ, tau in CSF)
- Brain imaging (MRI)
- Quality of life measures
This trial is actively recruiting participants. For more information, visit ClinicalTrials.gov NCT06189963.
- Unknown, SNK01 in Participants With Moderate Alzheimer's Disease (NKGen) (2023)