The killer instinct: Using natural killer therapy to treat Alzheimer’s

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DDW Editor Reece Armstrong speaks to Dr Paul Song, MD, NKGen and Dr Vince DeOrchis, clinician, to find out more about the investigational natural killer therapy SNK01 and the benefit of using a patient’s own cells to treat Alzheimer’s.

In October 2023, pharmaceutical company NKGen Biotech released data from its Phase I clinical trial on the use of its investigational natural killer therapy, SNK01, to treat patients with Alzheimer’s disease. Though the study was small and designed to primarily assess SNK01’s safety, data indicate that the therapy may do more than slow the progression of Alzheimer’s disease. The FDA has also granted Compassionate Use to SNK01 and the therapy is currently being used to treat a patient with Alzheimer’s.

RA: How does SNK01 work?

PS: Natural Killer (NK) cells play an essential role in maintaining human health and overall immune integrity. Unlike T cells that only have one receptor and thus cannot distinguish normal tissue from diseased or foreign tissue, NK cells have a range of receptors that they use to determine what is of ‘self’ and should be left alone or what is ‘not-of-self’ and should be eliminated (cancer cells, virally infected cells, renegade auto-immune cells that are attacking the host, and foreign bodies and proteins). Unfortunately, NK cells can become weaker with age or due to unhealthy lifestyle habits (stress, lack of sleep, poor diet, etc).

SNK01 is our proprietary autologous NK cell therapy where we harvest patients’ own NK cells and significantly multiply their number while greatly enhancing their overall cytotoxicity (killing potential) and upregulating their receptor expression. This is done without any genetic modification. The end result is the production of billions of highly enhanced powerful NK cells that can be given via intravenous infusion and cross the blood-brain barrier to help remove proteins like Amyloid, Tau, and alpha-synuclein and to reduce neuroinflammation.

RA: What are the clinical benefits of using the patient’s own cells as a treatment?

PS: Because we are using the patient’s own NK cells without any genetic modification, there are no drug-related adverse events, and patients can be treated indefinitely without any pre-treatment or lymphodepletion.

RA: What are some of the unmet needs in current treatments for Alzheimer’s?

PS: There is currently no proven treatment that either improves cognitive function or stops cognitive decline.

Most of the attention has been focused on a very small proportion of Alzheimer’s disease, those with mild cognitive impairment (MCI). And for all the attention that has recently been generated with the amyloid-targeted treatments, not one patient had any cognitive improvement, there was only some slowing of the rate of decline. While these drugs specifically targeted amyloid clearance, their success was largely dependent on the underlying level of p-tau protein levels. Patients with high levels of p-tau did not show any slowing of progression, regardless of how much amyloid levels were reduced.

RA: You’re targeting patients with a more advanced state of the disease rather than mild dementia or mild cognitive impairment (MCI). Why is this significant, and why are there currently no approved disease-modifying therapies for these patients?

PS: Most, if not all, current therapies are focused on MCI. The reason there are no treatments for the more advanced population is simply because there has been absolutely nothing that has been shown to work to date. We believe it is very important to focus on the more advanced populations who have largely been written off by the medical and pharmaceutical industries due to the lack of promise thus far.

RA: How encouraged are you by these Phase I data?

PS: Based on our initial Phase I data, we believe our approach shows tremendous promise for more advanced patients. In our Phase I dose escalation safety trial, we were able to see either real cognitive improvement and/or the stoppage of cognitive decline in a more advanced population (median mini-mental state examination (MMSE) score of 14) without any drug-related adverse events. We were also able to show a dose-response reduction in AB42/40, p-Tau levels in cerebrospinal fluid, as well as a reduction in neuroinflammation markers like GFAP (Glial fibrillary acidic protein).

RA: 90% of patients in the study maintained or showed improved cognitive function. Whilst only a small study, does this indicate to you that SNK01 could deliver further improvements in cognitive function?

PS: Yes, in this study, it was a proof-of-concept dose escalation study where we gave three different dose levels for only four total doses. Despite the fact that two thirds of our patients got very low doses, we had a 90% response (stable or improved cognitive function). In our Phase I/IIa study that the US FDA just cleared us to proceed with, we will be treating with a much higher dose (6 billion cells per infusion) and for a much longer duration (12 months versus 11 weeks). We believe this higher dosing and prolonged dosing schedule will lead to greater overall responses and improved outcomes.

RA: You’ve now received clearance for a Phase I/IIa study. What will be the goals from this study?

PS: Whereas our first trial was really a proof-of-concept trial designed to show safety and that our NK cells could indeed cross the blood-brain-barrier to reduce proteins and inflammation, this trial will be to show that an even higher sustained dosing will lead to real significant clinical improvement and/or stoppage of cognitive decline.

RA: As researchers in the field, what progress has been made for Alzheimer’s’ treatments?

PS: Sadly, a lot of work still needs to be done on the therapeutic side as there is still no treatment that actually improves cognitive function. However, a lot of progress has been made on the biomarker and genetic early detection area as well as on the imaging side with amyloid and tau-specific imaging. We remain optimistic that our novel approach will provide an entirely new paradigm in the treatment of this disease and other neurodegenerative diseases as well. We believe our treatment could also complement some of the other targeted antibody-based treatments too.

RA: Dr DeOrchis, as a clinician treating patients with Alzheimer’s, how limited are current treatments for Alzheimer’s and how much would you like to see new and more effective therapies be brought to market?

VDO: While the field has demonstrated great strides in more accurately diagnosing Alzheimer’s disease utilising clinical rating scales, CSF biomarkers, and novel imaging modalities, unfortunately, the landscape of therapeutic opportunities remains relatively unchanged as compared with what was available over 20 years ago. Certainly, no options have been presented that provide meaningful cognitive improvement in the moderate to advanced stage populations and even in the early stages of the disease, some of the recent pharmacologic options remain difficult to obtain, financially burdensome, and are associated with certain risks requiring frequent monitoring – all limitations that are difficult for the patient with cognitive impairment to navigate. Clinicians and patients eagerly await a therapeutic option that is safe, effective, and easy to administer. NKGen Biotech has demonstrated a novel and unique approach to combating this devastating and progressive neurodegenerative condition. Unlike the train of monoclonal agents that have come to market in the past few years, SNK01 attacks Alzheimer’s both by reducing the known toxic mediators, beta-amyloid and tau, as well as reducing cerebral inflammation, which appears to play a major role in neuronal dysfunction.

As an autologous transfusion, the product has been shown to be both safe and easy to administer. Additionally, recent data has shown both clinical improvement as well as a reduction in the concentration of toxic beta-amyloid and tau.

I remain hopeful that this new paradigm in pharmacologic therapies will finally provide a desperate population with safe, effective, and readily available treatment for Alzheimer’s type dementia.

DDW Volume 25 – Issue 1, Winter 2023/2024

Biographies:

Paul SongDr Song has served as Chief Executive Officer and Vice Chairman of NKGen since December 2022. He served as Chief Medical Officer of NKMAX, a public Korean biotech company that specialises in the development and manufacture of antibodies and proteins, from March 2016 to January 2021. Dr. Song co- founded and served as Chief Executive Officer and director of Fuse Biotherapeutics, a private immune-modulating therapeutics company.

Vince DeOrchisDr DeOrchis practices general neurology and has completed subspecialty training in Clinical Neurophysiology and Neuromuscular Disorders. He is certified by the Board of Psychiatry and Neurology as well as the American Board of Electrodiagnostic Medicine in EMG and neuromuscular ultrasound. He is also a Fellow of the American Academy of Neurology (FAAN).

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