The Power and Potential of Natural Killer Cell Therapies: A New Awakening

Alan Trounson, PhD, MSc

Alice Pébay, PhD

Walid J. Azar, PhD

Richard Boyd, PhD

What if the key to treating some of the most challenging diseases—ranging from cancer to neurological disorders—could lie within our immune system? Natural killer (NK) cells are the powerful yet often overlooked warriors of the immune system, playing a crucial role in defending us against infections and cancer. Traditionally known for their role in identifying and destroying infected or cancerous cells, NK cells are now being explored for a wide array of novel therapeutic applications. From tackling autoimmune diseases and fibrosis to offering new hope for conditions such as Alzheimer and Parkinson diseases, NK cells are proving to be more versatile—and more promising—than ever before.

NK cells are traditionally considered to be a key component of the innate immune system, their primary role being the cytotoxic control of invading pathogens, and cancerous cells and unhealthy cells expressing stress molecules due to infection or degeneration. They also have a regulatory role in interactions with T cells, macrophages, dendritic cells, and endothelial cells.¹ Their ability to discriminate between healthy and pathogenic cells makes them a useful vehicle for targeting cancer, fibrosis, endometriosis, and autoimmune disorders, and controlling a broad spectrum of disease conditions that may be driven by inflammation. Recently, NK cells were serendipitously found to be capable of neural repair, heralding a completely new therapeutic role.

Allogeneic cancer therapies involving NK cells are developing and include the addition of chimeric antigen receptors (CARs) that target tumor cells.² They may be isolated from adult and umbilical cord blood, followed by expansion ex vivo to clinically applicable levels. These systems have the disadvantages of batch-batch variability and cost. More recently, NK cells have been derived from induced pluripotent stem cells that can be functionally tailored by gene editing to introduce CARs and immune enhancement molecules or deleted of immune suppressive factors. The success of NK cells for control of solid tumors, however, is still evolving. One major distinguishing feature of CAR-NK cells relative to CAR-T cells is their high safety profile, making them an attractive prospect for pursuing other treatment modalities.

Expanding the Applications of CAR-T and CAR-NK Cells: From Fibrosis to Endometriosis

In this regard, the potential use of CAR-T therapies for lung and liver fibrosis is an important new development in these intractable diseases.³ The CAR targets fibroblast activation protein and appears to remove fibrotic lesions in models of cardiac failure in mice.⁴ These early studies are interesting because they may build wider applications of CAR-NK cells in the control of fibrosis.

Endometriosis is a challenging disease in women for which there are few therapeutic options beyond surgery and high-dose steroid treatment. Given that more than 10% of individuals assigned female at birth are affected by endometriosis, a condition that can lead to infertility, severe pelvic pain, and an increased risk of cancer, there is a critical need for effective therapies. In response to this growing demand, an Australian biotech company, Cartherics Pty. Ltd., is exploring the possibility of CAR-NK therapy using targets that are specific to endometriosis.

NK Cells in Neurological Disorders: A New Frontier in Brain Disease Therapy

Potential applications of NK cells also extend to neurological disorders. Inflammation and pathological protein accumulation in brain tissue are properties of Alzheimer’s disease (AD), Parkinson’s disease (PD), and traumatic brain injury (TBI). Interestingly, the company NKGen Biotech treated AD patients with ex vivo–activated autologous NK cells intended to boost their immune system, but surprisingly revealed some remarkable improvements in their AD condition, including cognition.⁵ Given the role of NK cells in the control of inflammation, it is likely that this may be a component of the therapeutic benefit observed in AD patients treated with activated NK cells.

As a result of the encouraging response to activated NK cells in the NKGen Biotech clinical studies in AD patients, the company is now expanding into an FDA investigational new drug application for a phase 1/2a clinical study to test the safety, tolerability, and exploratory efficacy of autologous NK therapy in AD patients.⁶ It is crucial to start investigating in more detail the mechanisms through which NK cells could influence not only AD but also other brain diseases characterized by neurodegeneration and neuroinflammation. The potential for cell therapies to address these conditions is particularly significant, given the limited treatment options available for many of these challenging disorders.

Indeed NK cells can be found in the central nervous system⁷ and form a major part of the innate immune system in the brain, together with microglia, which are macrophage-like. It has been shown that arming macrophages with a CAR specific for amyloid-b enables them to reduce plaques in vitro and ex vivo in mouse brain sections.⁸ Immune-deficient AD mice show increased amyloid pathology and an abundance of microglial cells with increased cytokine function, rather than phagocytosis ability, reflecting their dual role as part of the adaptive immune system.⁹ In a preliminary published report, the intravenous delivery of NK cells weekly for 5 weeks in AD model mice has shown reduced microglial activation, reduced amyloid precursor protein deposits, and reduced cognitive decline.¹⁰ These data further support a role of NK cells in AD. The logical next horizon is to potentiate the neurological specificity of these NK cells with a strategic CAR.

This growing understanding of NK cells' role in AD is paralleled by emerging research into their potential therapeutic effects in other neurological conditions, such as PD.

PD is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy bodies. These Lewy bodies contain the aggregated ⍺-synuclein (α-syn) protein, which can propagate prion-like from cell to cell and throughout different regions in the brain. NK cells can help remove α-syn proteins, reduce autoreactive T cell–generated inflammation, and remove damaged neurons. Mouse models of PD have shown α-syn aggregates reduce NK cell toxicity and that NK cells can clear α-syn deposits without aberrant activation.¹¹ NK cell depletion was associated with an increase in motor symptoms and ⍺-syn pathology, as well as dopaminergic neuron degeneration and increased neuroinflammation.¹⁰ NK cells have been found in the human central nervous system, in postmortem PD brains, including the substantia nigra, and leptomeninges.^10,12NK cells can recognize and clear senescent cells, reducing ⍺-syn load and proinflammatory cytokines. However, the levels of NK cells between healthy and PD brain samples reportedly remain similar.^10,13

Similarly, depending on severity, TBI can manifest as neurodegeneration and is associated with some similarities to AD, such as elevated tau protein in the brain, pro-inflammatory microglial activation, and astrocyte reactivity. As such, investigations into the effects of CAR-NK cells on disease biomarkers, immune cell activity, and behavorial alterations are a logical next step in the characterization of their effects in neurological disease states.

Unlocking the Full Potential of NK Cell Therapies

In conclusion, the growing recognition of NK cells as a versatile therapeutic tool marks a transformative shift in the landscape of medicine. Beyond their traditional role in immune defense, NK cells are emerging as a promising solution for a wide range of challenging diseases, including cancer, autoimmune disorders, fibrosis, and neurodegenerative conditions. With advances in cell therapy, particularly the development of CAR-NK cells, we are witnessing a new era of targeted, safer, and more effective treatments. As research continues and clinical trials expand, NK cells may well become a cornerstone of next-generation therapies, offering hope for conditions that have long lacked effective treatment options. The potential for NK cell therapies to revolutionize health care is immense, and we are only beginning to scratch the surface of their true capabilities.

REFERENCES
1. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503-510. doi:10.1038/ni1582
2. Pupovac A, Cao H, Trounson A. CAR-NK cells: promising for cancer therapy. Drug Target Review. November 17, 2023. Accessed November 25, 2024. https://www.drugtargetreview.com/article/112476/car-nk-cells-promising-for-cancer-therapy/
3. Sobecki M, Chen J, Krzywinska E, et al. Vaccination-based immunotherapy to target profibrotic cells in liver and lung. Cell Stem Cell. 2022;29(10):1459-1474.e9. doi:10.1016/j.stem.2022.08.012
4. Aghajanian H, Kimura T, Rurik JG, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573(7774):430-433. doi:10.1038/s41586-019-1546-z
5. NKGen Biotech presents updated NK cell therapy data for neurodegenerative disease at the 12th Annual Alzheimer’s & Parkinson’s Drug Development Summit. News release. NKGen Biotech. April 25, 2024. Accessed November 25, 2024. https://nkgenbiotech.com/nkgen-biotech-presents-updated-nk-cell-therapy-data-for-neurodegenerative-disease-at-the-12th-annual-alzheimers-parkinsons-drug-development-summit/
6. NKGen Biotech’s positive phase 1 clinical data in moderate Alzheimer’s disease advances troculeucel into phase 2 with first patient dosed in phase 1/2a trial. News release. NKGen Biotech. September 12, 2024. Accessed November 25, 2024. https://nkgenbiotech.com/nkgen-biotechs-positive-phase-1-clinical-data-in-moderate-alzheimers-disease-advances-troculeucel-into-phase-2-with-first-patient-dosed-in-phase-1-2a-trial/
7. Qi C, Liu Q. Natural killer cells in aging and age-related diseases. Neurobiol Dis. 2023;183:106156. doi:10.1016/j.nbd.2023.106156
8. Kim AB, Xiao Q, Yan P, et al. Chimeric antigen receptor macrophages target and resorb amyloid plaques. JCI Insight. 2024;9(6):e175015. doi:10.1172/jci.insight.175015
9. .Marsh SE, Abud EM, Lakatos A, et al. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A. 2016;113(9): E1316-1325. doi:10.1073/pnas.1525466113
10. Hwang DW, Sohn D, Ki YW, et al. Natural killer cells improve cognitive function and support to induce amyloid beta clearance by functional recovery of impaired microglia in natural killer cell-treated Alzheimer’s diseases mouse model. Alzheimer's & Dementia. 2022;18(suppl 10):e061720. doi:10.1002/alz.061720
11. Earls RH, Menees KB, Chung J, et al. NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy. Proc Natl Acad Sci U S A. 2020;117(3):1762-1771.doi:10.1073/pnas.1909110117
12. Hobson R, Levy SHS, Flaherty D, et al. Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration. bioRxiv. Preprint posted online July 14, 2023. doi:10.1101/2023.07.13.548931
13. Rodriguez-Mogeda C, van Ansenwoude CMJ, van der Molen L,Strijbis EMM, Mebius RE, de Vries HE.The role of CD56^bright NK cells in neurodegenerative disorders. J Neuroinflammation. 2024;21:48. doi:10.1186/s12974-024-03040-8