NK cell therapy seen to slow cognitive decline in Phase 1 trial

SNK01 was able to cross blood-brain barrier; lowered beta-amyloid, tau levels

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Treatment with SNK01, a natural killer (NK) cell therapy being developed by NKGen Biotech, appears safe and well tolerated and may offer a cognitive benefit to people with Alzheimer’s disease, according to data from a small Phase 1 clinical trial.

Given directly into the bloodstream, SNK01 was able to cross the blood-brain barrier, the semipermeable membrane that protects the brain and spinal cord, where it lowered the levels of beta-amyloid and tau, proteins that form toxic clumps in the brain of people with Alzheimer’s.

The company is also testing a higher dose of SNK01 against a placebo in a larger Phase 1/2 trial (NCT06189963) that will run for up to a year. The study may still be recruiting as many as 36 adults with moderate Alzheimer’s, ages 40-85, at a site in California.

“We are excited to continue our research with the goal of offering our NK cell therapy to patients with Alzheimer’s disease who are in need of [disease-modifying] treatments,” Paul Y. Song, MD, CEO of NKGen, said in a company press release.

Cognitive decline and other symptoms of Alzheimer’s develop due to toxic beta-amyloid plaques and tau tangles accumulating in the space between brain cells. This interferes with how the cells communicate with each other, leading to their death.

Immune NK cells recognize a wide range of other cells in distress and can help shape an immune response by clearing protein clumps. They’ve also been found to eliminate damaged neurons, or nerve cells, and regulate autoreactive immune T-cells, which may drive inflammation in Alzheimer’s.

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Testing SNK01 in Alzheimer’s

SNK01 contains NK cells derived from a patient’s blood. NKGen can grow and activate enough NK cells from a single collection to fulfill up to six months of treatment, according to the company.

NK cells can be frozen and stored before being infused back into a patient’s bloodstream. This should boost the immune response against what may be causing Alzheimer’s. Unlike other cell therapies, NK cells are less likely to drive an unwanted immune response.

The Phase 1 trial, called ASK-AD (NCT04678453), tested how safe SNK01 is when given every three weeks in four doses that gradually escalated from 1 x 109 to 4 x 109 NK cells. It also determined the highest tolerated dose to inform the Phase 2 trial design.

Secondary endpoints included changes in cognitive function, measured using validated clinical tools such as the Mini-Mental Status Examination (MMSE), and changes in the levels of beta-amyloid and tau proteins in the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, and blood over up to 22 weeks, or about five months.

The analysis included data from 10 adults (six women, five men) with mild to severe Alzheimer’s. Their median MMSE score was 14. In the MMSE, a score of 25 or higher indicates normal cognitive function. A score below 24 indicates possible cognitive impairment.

The data were presented by researchers from NKGen and Hospital Angeles in Tijuana, Mexico, in the oral presentation “Beneficial effect on CSF and plasma Tau proteins and cognitive function in Alzheimer’s disease subjects treated with expanded non-genetically modified autologous natural killer cells (SNK01)” during the Tau2024 Global Conference, March 25-26 in Washington, DC.

While most (70%) patients received low-dose SNK01, half had either a stable or improved MMSE score at one week after their last dose compared with the trial’s start, or its baseline. “One patient improved from MMSE score of 14 to 22,” the researchers wrote.

Similar results were obtained with the Alzheimer’s Disease Assessment Scale Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale: Sum of Boxes (CDR-SB), with up to 70% of patients remaining stable or improving.

In 90% of patients, the Alzheimer’s Disease Composite Score (ADCOMS), a more sensitive measure of cognitive decline, remained stable or improved. The effect lasted past the dosing, with a cognitive benefit observed for up to 22 weeks, or about three months after the last dose.

SNK01 is given by an injection into the vein, or intravenously, and appeared to cross the blood barrier into the CSF, where it resulted in decreases in the levels of beta-amyloid and tau as well as alpha-synuclein, a protein usually linked to Parkinson’s disease that can also accumulate in Alzheimer’s.

There were no treatment-related side effects. “SNK01 was safe and well tolerated” and “appears to have clinical activity in [Alzheimer’s],” the researchers wrote in an abstract to the presentation. “A larger trial with a higher dosing/duration has been initiated.”

“Our Phase 1/2a SNK01 trial in moderate Alzheimer’s patients, initiated in December 2023, utilizes a 50% higher dose than the highest dose administered in the prior Phase 1, and prolonged dosing regimen for over one year in which we expect to show an even greater clinical benefit,” Song said.