ONK therapeutics focus on the immune system’s innate ability to detect and eliminate diseased cells. These therapies center around Natural Killer (NK) cells, a powerful component of the body’s natural defenses. The goal is to harness these cells, enhancing their capabilities to combat various forms of cancer more effectively.
The Immune System’s Natural Killers
Natural Killer (NK) cells are a type of white blood cell, specifically a cytotoxic lymphocyte, and play a significant role in the innate immune system, which serves as the body’s first line of defense. These cells originate and mature in the bone marrow, but can also develop in other lymphoid tissues like lymph nodes, the spleen, and the thymus before circulating throughout the bloodstream. NK cells are distinct from T-cells and B-cells because they can identify and destroy abnormal cells, such as those infected by viruses or cancer cells, without requiring prior sensitization or specific antigen recognition.
This “natural” surveillance ability is attributed to their unique detection mechanism, which involves a balance of activating and inhibitory receptors on their surface. Healthy cells typically express major histocompatibility complex (MHC) class I molecules, which bind to inhibitory receptors on NK cells, preventing an attack. However, cancer cells often downregulate MHC class I expression to evade T-cell detection, inadvertently making them vulnerable targets for NK cells, which then receive fewer inhibitory signals. Upon recognizing a threat, NK cells release cytotoxic molecules like perforin and granzymes, which create pores in the target cell membrane and induce programmed cell death, known as apoptosis.
Harnessing NK Cells for Therapy
Therapeutic strategies involving NK cells enhance their ability to target and eliminate cancer cells. One approach is adoptive NK cell transfer, where NK cells are isolated, expanded, and reinfused into a patient. These cells can be sourced from the patient (autologous), a healthy donor (allogeneic), or induced pluripotent stem cells (iPSCs). Ex vivo expansion often involves stimulating NK cells with cytokines like interleukin-2 (IL-2), interleukin-15 (IL-15), or a combination of IL-12 and IL-18, which boosts their numbers and improves anti-tumor function.
Another strategy involves genetically engineering NK cells, notably through Chimeric Antigen Receptor (CAR)-NK cells. These engineered cells are equipped with CARs that enable them to specifically recognize and bind to particular proteins, or antigens, on the surface of cancer cells. This “built-in GPS” guides NK cells directly to tumor sites, enhancing their targeting precision and minimizing harm to healthy tissues. For instance, ONK Therapeutics is developing dual-targeted CAR-NK cells that combine a CAR with a tumor necrosis factor (TNF)–related apoptosis ligand (TRAIL) variant, activating a death receptor pathway in cancer cells for increased killing power.
Monoclonal antibodies are utilized to enhance NK cell activity through antibody-dependent cell-mediated cytotoxicity (ADCC). Here, therapeutic antibodies bind to cancer cells, and NK cells, which express the CD16 receptor, latch onto these antibody-coated cells, triggering their cytotoxic function. Researchers are also exploring methods to overcome the suppressive tumor microenvironment by genetically modifying NK cells to resist exhaustion or express additional molecules that enhance their persistence and anti-tumor effects, such as deleting checkpoint receptors or introducing genes like CISH knockout.
Clinical Development and Emerging Uses
ONK therapeutics are currently undergoing investigation across various clinical trial phases, showing promise in treating a range of malignancies. These therapies are being explored for both blood cancers, such as certain leukemias and multiple myeloma, and solid tumors, including hepatocellular carcinoma (liver cancer), non-small cell lung cancer (NSCLC), breast cancer, and ovarian cancer. A meta-analysis of 31 trials involving 600 patients showed favorable safety profiles, with fatigue being the most commonly reported adverse event.
Recent clinical data indicates encouraging objective response rates (ORRs) for NK cell therapies, particularly when combined with other local treatments. For example, in hepatocellular carcinoma, NK cell therapies combined with local therapies like irreversible electroporation demonstrated an ORR of approximately 72.3%. Allogeneic NK cells, derived from healthy donors, have shown superior efficacy compared to autologous cells, with an ORR of about 39.6% against 21.7% for autologous cells, largely due to donor-recipient incompatibilities in certain immune receptors that enhance anti-tumor activity. Ongoing research also includes studies on iPSC-derived NK cells, which can be mass-produced and engineered to target specific tumor antigens.
The Promise of NK Cell Therapies
NK cell therapies offer distinct advantages in cancer treatment. A primary benefit is their potential for “off-the-shelf” availability, meaning they can be manufactured in advance and stored, ready for use when a patient needs them, reducing logistical challenges and wait times associated with patient-specific cell therapies. This is largely because NK cells do not typically express the T-cell receptor, which mitigates the risk of graft-versus-host disease (GvHD) that can occur with unmodified donor T-cells.
NK cell therapies have a more favorable safety profile compared to other cell-based immunotherapies. They are associated with a lower risk of severe side effects such as cytokine release syndrome and neurotoxicity. Their ability to recognize and kill cancer cells without requiring specific major histocompatibility complex (MHC) matching offers broad applicability across different cancer types and patient populations. Ongoing research aims to further enhance NK cell persistence and function within the challenging tumor microenvironment, including the development of multi-gene edited NK cells that can overcome immunosuppression.