After Artiva Biotherapeutics announced the news of cryopreserved allogeneic NK cell therapies (AlloNK) for treating autoimmune disease, European Pharmaceutical Manufacturer spoke to Fred Aslan, M.D., president and chief executive officer, Artiva Biotherapeutics, to learn more.
Maks_lab Shutterstock
1. Can you elaborate on the differences in safety profiles between NK cell therapies and CAR-T cell therapies?
Natural killer (NK) cell therapies, such as Artiva’s AlloNK, present the potential for a significantly improved safety profile compared to CAR-T cell therapies. A major advantage of NK cell therapies is their lower incidence and severity of cytokine release syndrome and neurologic toxicities, which are common and sometimes severe side effects in CAR-T therapies. CAR-T therapies, particularly autologous CAR-T treatments, often induce intense immune activation, which can lead to dangerous inflammatory responses requiring hospitalization and intensive monitoring. In contrast, NK cells do not exhibit the same uncontrolled in vivo expansion as CAR-T cells, reducing the likelihood of severe systemic inflammation. Additionally, Artiva’s AlloNK is not genetically modified, eliminating concerns about secondary malignancies that have been observed with genetically engineered CAR-T cells. These advantages of NK cell therapies offer a more suitable option for outpatient administration, broadening access to cellular therapies for autoimmune diseases.
2. Are there specific types of autoimmune diseases where NK cells are particularly effective?
Autologous CAR-T therapy has demonstrated that profound B cell depletion can induce an “immune reset,” leading to sustained remission in severe autoimmune diseases. This finding, originally observed in oncology, has now been demonstrated in the autoimmune setting in both academic studies and through emerging data from auto-CAR-T companies. AlloNK can operate through the same fundamental mechanism of action—B cell depletion—by leveraging monoclonal antibodies to drive antibody-dependent cellular cytotoxicity (ADCC). This approach, currently in clinical trials, aims to replicate the success of CAR-T therapy while offering a more scalable and potentially safer alternative. If successful, AlloNK could be effective in B cell-driven autoimmune diseases such as systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, vasculitis, and pemphigus vulgaris. These diseases are characterised by pathogenic B cells that produce harmful autoantibodies, leading to tissue damage and chronic inflammation. By depleting B cells, AlloNK in combination with monoclonal antibodies has the potential to allow the immune system to regenerate healthy, non-pathogenic B cells, ultimately achieving long-term disease remission.
3. How does the lack of gene editing or genetic manipulation in NK cells affect their efficacy compared to CAR-T therapies?
Unlike CAR-T therapies, AlloNK does not require genetic modifications to effectively target and eliminate diseased cells. Instead, AlloNK leverages ADCC, in which monoclonal antibodies such as rituximab and obinutuzumab bind to target cells and recruit NK cells to induce cell death. This unique mechanism allows AlloNK to avoid the complexities and risks associated with genetic engineering, such as variability in manufacturing, potential unintended genetic alterations, and the risk of secondary malignancies. The absence of genetic modification also simplifies the production process, making NK cell therapies more scalable and cost-effective compared to CAR-T therapies, which require complex individualisation for each patient. Additionally, NK cells provide flexibility in targeting multiple B cell compartments by pairing them with different monoclonal antibodies, expanding their potential applications.
4. How do NK cells behave differently when targeting autoimmune diseases compared to targeting cancer cells?
NK cells function differently when targeting autoimmune diseases compared to cancer. In oncology, NK cells primarily act to identify and eliminate tumour cells through their natural cytotoxic mechanisms. In autoimmune diseases, however, the therapeutic goal is not to destroy malignant cells but to deeply deplete B cells to induce an “immune reset.” This process enables the immune system to regenerate a new population of B cells that lack the pathogenic properties responsible for autoimmune disease. Interestingly, despite the differences in disease pathology, the mechanism of action in both cancer and autoimmune diseases involves B cell depletion, as NK cells can be leveraged to eliminate aberrant B cells in both contexts—whether malignant B cells in lymphoma or autoreactive B cells in autoimmune conditions. The transient nature of NK cells is particularly advantageous in this setting, as they perform the necessary B cell depletion but do not persist long-term in the body, allowing normal immune function to be restored over time. This distinction makes NK cells well-suited for treating autoimmune conditions where durable remission is the objective, rather than continuous immune suppression.
5. What specific autoimmune diseases is AlloNK currently being tested on in the FDA-approved clinical trial?
Artiva’s AlloNK in combination with rituximab or obinutuzumab, an anti-CD20 antibody that targets B-cells, is currently being evaluated in an FDA-approved Phase 1/1b trial for systemic lupus erythematosus, including patients with lupus nephritis. In addition, AlloNK in combination with rituximab is being studied in an investigator-initiated basket trial in a community rheumatology practice that includes patients with rheumatoid arthritis, vasculitis, and pemphigus vulgaris. These trials aim to validate the ability of AlloNK, when combined with monoclonal antibodies, to deplete B cells effectively and induce lasting immune reset in a range of autoimmune conditions. The inclusion of multiple diseases in the basket trial reflects the broad potential of NK cell therapy across autoimmune indications where B cell depletion has already shown promise.
6. What is the long-term vision for scaling AlloNK further, considering demand and global distribution challenges?
Artiva’s long-term vision for AlloNK revolves around scalable, cost-effective manufacturing to meet the growing demand for NK cell therapies. The company has adopted a “manufacturing-first” approach, ensuring that its production platform is capable of producing large quantities of NK cells while maintaining product consistency. AlloNK is derived from umbilical cord units, allowing a single cord to produce thousands of vials, significantly reducing manufacturing costs. This approach is expected to make NK cell therapy more accessible and affordable compared to CAR-T therapies, which are highly individualised and costly. Artiva’s goal is to establish AlloNK as an off-the-shelf, outpatient-administered therapy, enabling its use in community settings rather than requiring specialised hospital centres. By prioritising scalability and broad accessibility, Artiva aims to position AlloNK as a leading cell therapy for autoimmune diseases worldwide.