Could Chimeric Antigen Receptor-NK Cell Therapy Be the Next Big Thing?

Natural killer cells, which kill tumor cells in multiple ways, could provide a shakeup in the fight against cancer

For the last few decades, our understanding of how to harness the power of the immune system to fight tumors has grown rapidly. With the help of immunotherapies, such as checkpoint inhibitors, and more recently chimeric antigen receptor T-cell therapy, previously advanced and, in some cases refractory cancers, have now become treatable. However, chimeric antigen receptor (CAR) T- cell therapy is not without its drawbacks, not least the cost to produce these individualized cellular therapies for each person, but also the side effects including cytokine release syndrome (CRS), neurotoxicity and graft versus host disease (GvHD). More recently, knowledge gained from CAR T-cell therapy has contributed to the scientific community turning their attention to another powerful cytotoxic lymphocyte, the natural killer (NK) cell, in the hope of overcoming some of these limitations.

NK cells are a unique subtype of innate lymphoid cell that represents ~10-15% of the total peripheral lymphocyte pool and are functionally critical in patrolling for malignant and virally infected cells. Unlike CD8+ cytotoxic T cells, NK cells do not require activation via a T cell receptor (TCR) or recognize antigen presented via the Major Histocompatibility Complex (MHC) class I. In fact, they recognize MHC I expressed on healthy cells and avoid attacking them. In contrast, they become activated and kill tumor cells that have downregulated their MHC I to evade CD8+T cell immune surveillance. It is these intrinsic biological features which make them an ideal candidate to generate cell therapies from allogenic (genetically dissimilar) HLA-incompatible donors as they do not cause GvHD.

Why are natural killer cells a good therapeutic? 

The full reasons behind why NK cells do not cause GvHD are not totally understood, though the expression of specific cell surface inhibitory and activatory receptors on the NK cell surface are likely to underpin the effect. Nonetheless, this does mean that NK cells have a superior safety profile to allogenic T cells and present the idea of an off-the-shelf therapy that would save time and money and satisfy the requirement for large-scale production.

It is these attributes that make NK cells so attractive as a therapeutic, and with the ability to generate CAR-NK, creates the ideal candidate for a successful adoptive cellular immunotherapy. So far, multiple sources have been used to create CAR-NK: the NK92 cell line, peripheral blood mononuclear cells, umbilical cord blood, hematopoietic stem and progenitor cells and induced pluripotent stem cells. All are amenable to CAR receptor engineering, and all are being trialed in humans. However, each cell source comes with its own characteristics and functional properties and thus all present with different opportunities and weaknesses.

Despite the advantages of CAR-NK cells, there are a few hurdles that still need to be overcome. Due to the limited number of NK cells in the blood, and the fragility of the cells post- cryopreservation, ex vivo expansion methods that do not induce cell exhaustion and maintain cytotoxicity, in combination with inflammatory cytokine production, are required. Additionally, NK cells are known to be difficult to engineer and the paucity of an efficient gene transfer technology remains a vital stumbling block in the production of novel CAR-NK therapies.

Will CAR-NK cells be a durable treatment? 

The jury is also still out on whether CAR-NK cells persist post infusion. Since the first CAR-NK trials in 2009, studies have shown safety and efficacy for several hematological malignancies, but their lifespan is thought to range between 1-4 weeks. This could be overcome by repeat infusions. More recently with the new generations of CAR, NK priming, and persistence has been markedly improved and CAR-NK cells can be engineered to produce cytokines that support this. As a result, one trial testing a CD19 CAR-NK therapy, engineered to express the cytokine IL-15, from the MD Anderson Cancer Centre (USA), reported a 73% response rate within one month following transfusion, with persistence confirmed one-year post-infusion. To date, there are 39 clinical trials registered assessing the safety and efficiency of CAR-NK cells in the treatment of malignancies and the majority are yet to finish. Interestingly, emerging from the success of CAR-NK for treatment of malignancies, are also CAR-NK cells that are being engineered to exploit their viral cytotoxic ability. Pre-clinical models have demonstrated CAR-NK (directed against the Spike protein of SARS-CoV-2) were effective in treating mice infected with COVID 19. A Phase I clinical trial began recruiting in 2020 but has yet to report.

Whether CAR-NK cells are more or equally effective to CAR-T therapy remains to be determined. However, the ability of CAR-NK to penetrate into solid tumors, and their inherent recognition of tumor markers in combination with CAR-mediated mechanisms makes them an attractive prospect. Multiple strategies including the ability to upscale production and to enrich a pure population of CAR-NK cells are required to significantly expand the field but will hopefully lead to a substantial improvement in patient survival. It is not inconceivable that an off-the-shelf CAR-NK product could be used in the short term to treat patients whilst a personalized CAR-T is being produced, with CAR-T forming a second line treatment.

In conclusion, CAR-NK cells are rapidly emerging as a promising alternative cellular therapeutic with improved efficacy and reduced adverse effects. Harnessing the immune system to treat cancer (and possibly viral infections) is hugely powerful and CAR-NK are likely to form a critical part of this.

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Dr. Karina Di Gregoli, PhD,  is a Team Leader in the Cell Biology Division at Charles River Laboratories in Portishead, UK. She is currently contributing to developing CAR-NK cell therapy. Before joining CRL Charles River Laboratories in 2021, Karina worked extensively on the role of innate immunity in the development and progression of coronary heart disease at the Bristol Heart Institute (University of Bristol, UK).

Dr. Lauren Schewitz-Bowers, PhD, is a Group Leader in the Cell Biology Division at Charles River Laboratories in Portishead, UK. She is currently leading the team developing CAR-NK cell therapy. Previously, Lauren worked extensively on immunotherapeutic target and biomarker discovery in line with one of the NIHR – Biomedical Research Centre’s strategic themes of personalizing medicine. She joined the Cell Biology team at Charles River Laboratories in 2019 bringing her knowledge of immunotherapy drug target development within an in vitro setting and oversees several early-stage research and discovery studies for multiple clients.