Treating Alzheimer's With NK Cell Therapy
By Tyler Menichiello, contributing editor
Natural killer (NK) cell therapies represent a growing segment of the cell and gene therapy market, one largely concentrated in the field of cancer immunotherapy. Like most companies in the space, NKGen Biotech’s focus was on developing an NK cell therapy for cancer patients. That is, until several compassionate use cases revealed that NK cells may also have the potential to treat patients with Alzheimer's disease. Now, the company is running a Phase 1/2a clinical trial in the U.S. to evaluate the efficacy of its autologous NK cell therapy, SNK01, in patients with Alzheimer’s.
To learn more about how a serendipitous discovery shifted the company’s clinical focus, I met with NKGen’s CEO, Dr. Paul Song, MD. He walks me through the early findings that shed light on NK cells’ potential to treat neurodegenerative diseases, as well as how the company conducted an initial Phase 1 trial in Mexico to prepare for its Phase 1/2a trial in the U.S.
Realizing A New Indication
Song is an oncologist by training, and before any thought of Alzheimer’s disease, the company’s primary focus was on developing an autologous NK cell therapy for cancer patients. More specifically, its focus was on developing a manufacturing process to strengthen a patient’s own NK cells to fight their cancer, without genetic modification. “We started trials in cancer, and things were going very well,” Song says. “We’d shown that our cells were safe because they’re not genetically modified, and there were no side effects associated with our treatment.”
Sangwoo Park is the founder of NKGen, and around this time, his father was in poor health at a nursing facility in Seoul, South Korea — bedridden and hardly able to talk or move. “He was worried that his father was going to get an infection, and he asked me if it would be worthwhile to give him some enhanced NK cells to boost his immune system,” Song tells me. Deciding it was worth a shot, NKGen treated Park’s father.
After several treatments, not only did his father’s condition improve, but he became more cognitively aware and alert. Park told Song excitedly, “you’re not going to believe this, but my father is talking to me! He hasn’t said a word in years!” This unexpected improvement prompted Song to pore over the literature in search of any precedent on the role of NK cells in treating Alzheimer’s disease. “I reached out to some of my friends who are neuroscientists, and all of them said no, it doesn’t make any sense. That was probably just a coincidence,” Song says. “So, we somewhat put it on the backburner.”
And on the backburner it remained, until an employee learned about a family friend (a 38-year-old) with advanced Alzheimer’s disease. “By the time we met him, he was in hospice requiring 24-hour care,” Song tells me. NKGen offered to treat this man under compassionate use, and the family agreed. Prior to receiving treatment, the patient was evaluated by Dr. Ming Guo, an Alzheimer’s disease researcher at UCLA. “After the examination, she said this was one of the worst cases she had ever seen,” Song recalls. “His condition was so advanced that he couldn’t even hold a pen or talk, so she couldn’t do a mini-mental status exam.” After three treatments, Song says, the man was able to walk, talk, and even use chopsticks to feed himself.
He recounts another story about a woman in New York who experienced a similar improvement post-NK cell treatment. “Based on all of those initial experiences that I’m not cherry picking, we felt there was something there, but we just couldn’t fully understand the mechanism of action,” Song says. Despite a lot of doubt among investors who felt that NKGen should “stay in its lane” and stick to cancer research, the company continued to investigate the underlying science behind these unprecedented responses. “We publicly continued on our cancer route, but privately, we were really working hard to figure things out.”
A Roundabout Path To U.S. Clinical Trials
According to Song, NKGen’s autologous NK cell therapy is viewed as a treatment in many countries (e.g., Japan, Thailand, and Mexico), not a drug, because the cells are not genetically modified. Since NKGen didn’t have a good animal model at the time, Song says the company decided to go to one of these countries to conduct a trial legally. With the intent of doing so in Mexico, the company’s strategy was to conduct a Phase 1 trial and collect sufficient data to bring back to the U.S. FDA.
“Even though we didn’t need Mexican FDA approval, we still put together a protocol that was vetted through the Mexican FDA,” Song explains. “We wanted show the U.S. FDA that this was done under good clinical practice.”
In Mexico, the company completed a Phase 1, dose-escalation trial in patients with Alzheimer’s disease. Throughout the study, NKGen collected biomarker data — which involved lumbar punctures to measure neuroinflammatory markers and protein levels in cerebrospinal fluid — and performed cognitive testing throughout. This data was presented at both the Alzheimer’s Association International Conference in Amsterdam and the Alzheimer’s Disease Conference in Boston.
“We showed that when we take someone’s own NK cells, activate and expand them, and give them back to patients through an IV, that they can cross into the brain to reduce all amyloid-beta proteins, tau proteins, and alpha-synuclein proteins, as well as reduce neuroinflammation,” Song says. The majority of patients treated either improved or remained stable. To put that in perspective, he says, the current standard-of-care drugs slow disease progression, but patients still continue to get worse over time.
“We took all that data to the U.S. FDA, as well as the Canadian FDA, and we just got clearance to move forward with our Phase 2 trial,” Song tells me. Now, he says, sites that doubted NKGen’s approach are reaching out to be involved in the clinical trial.
Changing The Perception Of NK Cells
According to Song, the therapeutic effect seen in these patients is likely due to NK cells’ ability to remove protein aggregates in the brain, while at the same time, reducing neuroinflammation. He says a lot of the current drugs for Alzheimer’s accomplish that first part, but not the second. “If you just remove the proteins but leave all this inflammation and damage behind, we argue that’s one of the reasons why these current drugs are not really working,” he says.
Song hopes NKGen’s work in Alzheimer’s will reinvigorate the industry’s interest in NK cells and shine light on their potential to treat human diseases beyond oncology. “I think the NK sector has lost a lot of luster over the last few years,” he says. “Most of the companies set out to establish CAR-NKs targeting a specific tumor antigen, and I would say the majority of those treatments have really fallen short of expectations and certainly have not done better than CAR-T.” He says NKGen’s ultimate goal for SNK01 is to treat patients with Alzheimer’s in the earlier stages, or even as a preventative therapy. “Like an oil change,” he says, describing a future where patients at high risk or predisposed to Alzheimer’s receive treatment several times a year.