Autologous Natural Killer Cells Hold Potential as Novel Treatment for Parkinson Disease

This is the second part of an interview with Paul Y. Song, MD. For the first part, click here.

Paul Y. Song, MD
Credit: NKGen

NKGen Biotech is currently evaluating SNK01, an investigational autologous natural killer (NK) cell therapy originally developed for oncology indications, for the treatment of both Alzheimer disease (AD) and Parkinson disease (PD). Notably, the FDA cleared an investigational new drug (IND) application for SNK01 in PD in April 2024.

Shortly after NKGen announced the IND clearance, CGTLive spoke with Paul Y. Song, MD, the chairman and chief executive officer of NKGen, to learn more about the cell therapy in the context of PD. Song described how the company came to discover the potential of SNK01 in neurodegenerative disease and the promise it has shown so far in a compassionate use context.

CGTLive: What is SNK01 and how may it help to address unmet needs in PD?

Paul Y. Song, MD: SNK01 is an autologous, enhanced NK cell therapy. Essentially, NK cells are very, very difficult to get to grow. This is why most of the companies that are in this space have focused strictly on using an allergenic or universal donor to treat cancer. When we set out to develop our platform, we were very interested in cancer and we still have trials going on in cancer. But we felt that if you look at the literature there are thousands of publications that correlate weak or deficient NK cells with various diseases—whether it be autoimmune diseases, susceptibility to cancer, even autism—there's a lot of data emerging that these patients who have active diseases have weak NK cells. So we wanted to set up a way that we could take anyone's NK cells, no matter if they were from a healthy subject or heavily pretreated cancer patient or somebody who had chronic autoimmune disease, and take the NK cells and grow them into massive quantities—but not only grow them into massive quantities—if you have weak or deficient NK cells and all we're doing is making more weak and deficient NK cells, we would argue that's not going to be biologically beneficial to the patient. So the second thing we're able to do is dramatically increase the killing potential, or what we call the cytotoxicity of NK cells. Then the third thing is that unlike T-cells that only have 1 receptor, NK cells have 40 receptors. Think of a blind person who uses their fingers to read braille. In much the same way NK cells use these receptors as they police your body to determine what's normal healthy tissue that should be left alone or what is sort of diseased—whether it be a cancer cell, a virally infected cell, a protein, or even a renegade T-cell that's attacking one's own body. Through these receptors, the NK cells can distinguish what should be there and what should be eliminated. But in the normal human healthy condition sometimes as we get older, our immune systems get weaker. If we've been under a lot of stress or haven't had enough sleep or have unhealthy lifestyle changes, again, that can affect your immune system. So sometimes the NK cell may have the receptors, but as it approaches something that it knows shouldn't be there it may not have the killing potential or the power to eliminate it. On the other hand, sometimes the NK cell may have the strength behind it, but not have the ability to really discern whether or not something's normal or diseased. So we're really not genetically modifying anyone cells, but we are optimizing them to our inherent potential that was always there by taking people's NK cells, putting them through a process, growing them into billions of cells that are highly enhanced (both in terms of killing as well as sensitivity) and we give these back to patients.

Then we also found that when we take cells, particularly in our Alzheimer disease (AD) study—when we measure them for a certain receptor that they need in order to allow the NK cell to cross into the brain, most healthy patients even when you take the cells from the patient in the beginning don't have what we call a chemokine receptor. But after we've had a chance to put it through our process, we see upregulation of this chemokine receptor that is required for NK cells to then be able to traffic into the brain. This is one of the ways we've been able to show our NK cells do cross the blood-brain barrier and can start to effect all these positive changes.

What are some of the challenges of bringing a cell therapy like SNK01 to PD? And how can these challenges be overcome?

Well, the biggest challenge was when we first started to propose this, because there was no prior precedent and there was no ivory tower that had been doing such work, everyone thought it didn't make sense. They thought it was nonsensical. The skepticism that we had was really, really pretty extreme.

So we really just had to put our heads down, figure out the mechanism of action, get the corresponding biomarker data, as well as clinical outcome data, to then be able to present this at meetings. And now we went from nobody believing what we do to having major institutions all wanting to be part of our trial.

Same thing, when we first started to look at this a few years ago, it was by serendipitous discovery in that we initially tried to boost the immune system of somebody with advanced AD who was at very high risk of developing an infection, not knowing that our NK cells could have these other effects. When we started to see profound improvements in cognitive function and then we tried this in other patients, we felt like we needed to try to figure out what was going on. So unlike the traditional way, where somebody has a hypothesis, they test it in a petri dish, and then an animal, and then in a human—we happen to find that when we gave these cells to patients with advanced AD, and a few advanced PD patients, that they were starting to feel and show real improvement, both in terms of neuro function as well as cognitive function. We then we had to figure out and work backwards as to why we were seeing what we were seeing. And again, we've now done subsequent studies to show that our NK cells can not only identify amyloid proteins and tau proteins and α-synuclein proteins, but they can actually phagocytose and then readily digested these proteins, as well as human microglia. Then also, again, they can identify and eliminate these autoreactive T-cells to cool off the brain. We showed these in several models. Then more importantly, we were able to substantiate that with human biomarker data. Then ultimately, we translated that into real meaningful disease modifying effects in patients. Based on all that, we submitted the data to the US FDA, and they felt very confident in green lighting our IND for PD. We're very excited to get that trial up and running next quarter and really show that we can make a real impact in a disease that—again, a lot of the therapies out there control the symptoms, but nobody seems to get better and eventually with time people become refractory. Part of what drives me is a dear friend of mine has had early onset PD. He was diagnosed in his 40s and has been very rigorous about his exercise routine, which we know seems to help, taking his sinemet, but now things have become more refractory and we've actually treated him a few times with SNK01 in a compassionate use context. He's shown real dramatic improvement with this. Based on all this, we felt a strong enough signal existed and a strong enough scientific rationale to now really move forward with this trial.

Transcript edited for clarity.

REFERENCES
1. NKGen Biotech announces FDA clearance of investigational new drug (IND) application for SNK01 NK cell therapy in Parkinson’s disease. News release. NKGen Biotech, Inc. April 30, 2024. Accessed April 30, 2024. https://nkgenbiotech.com/nkgen-biotech-announces-fda-clearance-of-investigational-new-drug-ind-application-for-snk01-nk-cell-therapy-in-parkinsons-disease/