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By Richard Boyd PhD and Alan Trounson PhD
Natural Killer (NK) cell therapies are rapidly emerging as a transformative force in healthcare, with promising potential across a range of conditions. They feature the complex killing capacity of classic immune system T cells but lack the prolonged time required for them to respond. With the armoury to rapidly detect and remove damaged, infected, senescent and cancerous cells throughout the body, they are nature’s frontline cell-mediated attack force. This capability has sparked considerable interest in developing NK cell-based therapies for cancer treatment and other conditions. Over time, NK cell therapies have evolved from early-stage research to a promising and advanced area of immunotherapy. From the discovery of NK cells’ innate ability to target abnormal cells, to the advent of CAR-NK cells and combination therapies, these treatments have made significant strides. With researchers continuing to address challenges such as solid tumour treatment, NK cell persistence, and scalability, NK cells are poised to play an increasingly important role in the future of medicine and the treatment of various cancers, inflammatory diseases, and even neurological disorders.
While the source of NK cells for clinical therapies has primarily been from adult or newborn blood, the multiple impracticalities of this approach have precluded their clinical utility. However the development of NK cells from pluripotential stem cells as a continuous renewable source and conveyance of target specificity through Chimeric Antigen Receptor (CAR) technology has transformed their widespread therapeutic potential. From the development of allogeneic CAR NK cell treatments for cancer to the role of CAR-NK in fibrosis and endometriosis, and even their impact on neurological disorders, NK cells are poised to revolutionise therapeutic approaches. This article explores the latest advancements and the exciting future of NK cell-based treatments.
NK cells are a type of white blood cell that play a crucial role in the body’s innate immune defence mechanisms. They are best known for protecting against tumours and infections by targeting and killing abnormal cells. As distinct from lymphocytes of the adaptive immune system, NK cells are endogenously primed for immediate responses; they can detect potentially pathological changes in “self cells” and remove them rapidly before disease sets in. However they are relatively short-lived. On the other hand, T lymphocytes require a complex array of induction pathways to be engaged before they become functional effector cells, but having “passed” the activation hurdles, T cells provide long-term protection. This segregates the two classes of immune cells in terms of clinical application. T cells are targets of vaccination to provide life-long immunity typically to viruses or bacteria. The practical problem with T cells is their limited number; their organ of origin is the thymus and this paradoxically atrophies from early puberty. Giving patients the large number of T cells required, involves collection from an allogeneic source. This runs the severe risk of graft-versus-host disease (GVHD) and patient safety concerns.
Advancements in Allogeneic NK Cell Therapies: Off-the-Shelf Treatments and the Promise of iPSC-Derived NK Cells
One of the most exciting advancements is the development of allogeneic NK cell therapies. By using NK cells from healthy donors (allogeneic), rather than from the patient’s own immune system, these therapies offer the advantage of off-the-shelf treatments that are ready for immediate use. Mature NK cells may be isolated from adult and umbilical cord blood, followed by expansion ex vivo to clinically acceptable levels.
As distinct from T cells, NK cells do not recognise major histocompatibility complex (MHC) molecules and hence do not manifest GVHD against the host (patient). NK cells also only have short-term survival, minimising and risk of developing their immune rejection by the host. If this rejection did occur, the patient would be effectively immunised against those donor cells; they could not be subsequently given to that patient.
Accordingly, several studies indicate that NK cell therapies are generally considered safer than CAR-T cell therapies, due to their lower risk of severe side effects like cytokine release syndrome (CRS) and GVHD. This allows for allogeneic (donor-derived) infusions without major immune reactions; this is supported by clinical trials demonstrating favourable safety profiles when using NK cells in cancer treatment, including studies utilising CAR-engineered NK cells. [i] [ii] [iii]
NK cells are thus much safer than T cells but being short-lived require multiple infusions of large numbers of cells. The resolution to this paradox of requiring safer but equally functional properties of NK cells, lies in the development of technologies for creating NK cells from induced pluripotential stem cells (iPSC).
Advantages of iPSC-Derived NK Cells
Unlike traditional allogeneic sources, which rely on a finite number of healthy donors, iPSCs can be derived from a single starting cell line and expanded indefinitely in the lab. This provides a sustainable and scalable source of NK cells, overcoming the limitations of donor variability and availability. As a result, iPSC-derived NK cells can be produced on-demand, reducing the reliance on finding compatible donors and enabling faster, more efficient, production of therapeutic cells, making them a highly promising option for widespread clinical application.
Indeed, iPSC have multiple advantages: they replicate indefinitely, theoretically providing a limitless source of effector cells; they can be induced into highly functional NK cells; they can be genetically sculptured for functional precision in the NK cells. Furthermore, edited iPSC can be cloned and expanded as a Master Cell Bank from which NK cells can be derived in large numbers. Hence iPSC-derived NK cells (iNK cells) offer a level of uniformity and consistency that traditional allogeneic NK cells cannot match. Being scalable “off-the-shelf” NK cells, it overcomes the challenges related to donor availability and variability, thereby offering the potential for more personalised and accessible treatments.
Because iPSCs are derived from a single cell line, the resulting iNK cells exhibit highly consistent characteristics in terms of quality, function, and purity. This consistency is crucial for ensuring the reliability of treatments, as variations in NK cell properties can affect therapeutic efficacy and safety. The ability to produce large quantities of uniform NK cells reduces the variability seen in donor-derived NK cells and ensures that each patient receives a treatment that meets the same high standards. Additionally, allogeneic NK cell therapies have the potential to lower costs and simplify the manufacturing process, making them a highly promising option for widespread clinical application.
The Australian biotech company, Cartherics Pty Ltd has a novel technology for inducing iNK cells from iPSCs. Cartherics recognises the importance of the iNK differentiation recapitulating that which naturally occurs in vivo. This entails the primary step being to program the iPSC into the haemogenic lineage which gives rise to haemopoietic stem cell (HSC)-like cells; HSC are the ultimate source of lymphoid cells including NK cells. A distinguishing feature of the Cartherics in-house method of manufacture within a new purpose-built 1,800m2 R&D facility, is the development of 3D culture systems and Bioreactor technologies. This allows for optimal inter- and intra-cellular signalling similar to that occurring in vivo. This is fundamentally important for functional and safety properties of the final iNK cells, in addition to achieving their required numerical output, which has a big bearing on the therapy economics. Cartherics’ scalable technology enables production of many billions of iNK cells, meeting on-demand availability for patients. This iNK cell manufacture is without the need for feeder cells, meaning zero risk of support cell contamination, avoiding the additional costs and complexity to manufacture multiple cell lines.
Cartherics has further improved this iNK function by genetically engineering its iPSCs so that the iNK cells express a cancer specific CAR. In addition, Cartherics deletes important immune suppression genes. In normal healthy individuals these immune “hand-brakes” maintain homeostasis, but in the cancer setting, they are best “silenced” to facilitate maximal cytotoxicity.
One of the key challenges facing cellular immunotherapy is functional penetration of the immune suppressive tumor microenvironment (TME) in solid tumors. The body’s natural response to a developing tumor is to engulf it with fibroblasts as it would any inflammation. Paradoxically this has a dual effect: it promotes tumor cell growth and hinders immune function (the latter no doubt facilitating the former). Cartherics is developing novel approaches to overcoming the protective cell barrier.
The Potential of iPSC-Based NK Cell Therapies Across Many Major Medical Conditions
Despite their huge potential in the field of cancer therapy, NK cells are arousing international interest in some surprising clinical applications which embrace some of the most challenging of diseases. Cartherics has established important collaborations with prominent national and international opinion leaders to adapt its core genetically engineered iPSC platform to explore these opportunities.
Endometriosis, for example, has no cure and is a devastating, painful condition affecting the health and fertility of many millions of women; it is emerging as a novel target for NK cells. This is based not only on the primary feature of NK cells being to recognise abnormal cells, but Cartherics has shown they can be functionalised by genetic addition of CARs targeting specific molecules on the endometrial cells.
Very recently, NK cells, have emerged as a potential therapy for neurological disorders of great magnitude including Alzheimer’s (AD) and Parkinson’s (PD) diseases, Again the common denominator is the inherent ability of NK cells to recognise abnormal cells. However it is now becoming evident that NK cells may degrade β-amyloid plaques in AD and α-Synuclein in PD, via complex interactions with brain microglia.
Reflecting their capacity for controlling inflammation, NK cells are also being explored by Cartherics for potential treatment of traumatic brain injury (TBI), a major concern in accidents and concussion in many contact sports.
The company’s lead CAR-NK cell therapy product, CTH-401, is set to initiate clinical trials this year in ovarian cancer. The company is also expanding its pipeline to include iT cells and imacrophages.
In addition to Cartherics, several leading companies and academic institutions are driving advancements in iPSC-derived NK cell therapies, making significant strides in the development of scalable treatments for a variety of diseases. Notable players in this space include: Fate Therapeutics, Century Therapeutics, Caribou Biosciences, Artiva Biotherapeutics, CytoLynx Therapeutics.
The future of iPSC-based NK cell therapies holds immense promise across a wide range of medical conditions. By harnessing the potential of iPSC, researchers are paving the way for more scalable, personalised, and effective treatments for diseases like cancer, fibrosis, endometriosis, and neurological disorders. These therapies offer the ability to create targeted, customisable NK cells that can be engineered to attack specific disease markers, providing a precision medicine approach to conditions that have long been challenging to treat. As iPSC-derived NK cells continue to advance, they could revolutionise how we approach immune disorders and chronic diseases, offering new hope for patients worldwide.
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Emeritus Prof. Alan Trounson is the Chief Executive Officer and Dr. Richard Boyd is Scientific Advisor of Cartherics Pty Ltd, an Australian biotech company developing immune cell therapies for the treatment of solid cancers and other diseases.
[i] Marofi, F., Saleh, M.M., Rahman, H.S. et al. CAR-engineered NK cells; a promising therapeutic option for treatment of hematological malignancies. Stem Cell Res Ther 12, 374 (2021). https://doi.org/10.1186/s13287-021-02462-y
[ii] Hodgins JJ, Khan ST, Park MM, Auer RC, Ardolino M. Killers 2.0: NK cell therapies at the forefront of cancer control. J Clin Invest. 2019 Sep 3;129(9):3499-3510. doi: 10.1172/JCI129338. PMID: 31478911; PMCID: PMC6715409.
[iii] Page, A., Chuvin, N., Valladeau-Guilemond, J. et al. Development of NK cell-based cancer immunotherapies through receptor engineering. Cell Mol Immunol 21, 315–331 (2024). https://doi.org/10.1038/s41423-024-01145-x/
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