Natural Killer (NK) cells have a unique role of detecting and destroying malignant and virus infected cells (Kiessling 1981) as a part of the immune system. The role of NK cells in the treatment of leukemia has been demonstrated in the context of hematopoietic stem cell transplantation (Ruggeri 2002, Ruggeri 2008). These findings support the use of allogeneic NK cells for treatment of patients and clinical responses have been observed (Miller 2005, Rubnitz 2010, Curti 2017, Dolstra 2017). Clinical-grade NK cell products can be generated by a growing variety of methods resulting in donor NK cells with different phenotype and function amendable to different clinical applications.
NK cell products made by different methods could be administered to a single patient with specific donor/recipient matching requirements, or the products could be manufactured in industrial-scale for universal “off-the-shelf” dispensation. These methods have different potential to scale from small phase I trials to treatment of hundreds of patients with an approved cell therapy product. NK cell products thus can cover the needs from individualized medicine to universal products.
Starting materials to generate clinical NK cell products include human whole blood, apheresis harvests, umbilical cord blood, NK cell lines, induced pluripotent stem cells and hematopoietic stem cells, with varying availability and protocol requirements, receptor repertoire and function.
Genetic modifications of immune cells have raised great interest for patient treatment due to high clinical response rates for patient T cells modified with chimeric antigen receptors. Serious side effects have been observed, prompting the clinical development of “safer” immune effector cells. Genetic modifications can generate NK cell products with novel functionality, including specificity of target cell recognition, signaling, reduced inhibition, improved survival or additional protein secretion. NK cells have a natural reactivity against viruses and thus have been described to be relatively resistant to genetic modification by viral particles. Methods have been developed to successfully modify NK cells or their progenitors.
Manufacturing of NK cell products for patients requires the use of appropriate reagents, disposables and environments to fulfill the needs for regulatory acceptance for clinical application. Closed systems can support manufacturing of NK cell products in a clean room at lower grades. They also require validation of the closed system.
Overall, a large range of methods to “produce” NK cells in high quantity and with high functionality has been developed, successfully translating basic research into GMP procedure and use in clinical trials.
This Research Topic reviews current methods to provide NK cells for treatment of patients, their phenotype and function and their uses in patient treatment. Individual methods are described in details and new approaches are proposed for further translation into GMP protocols.
Dr. Huppert is employed by Glycostem Therapeutics B.V. Dr. Leung is a part-time employee of Miltenyi Biotec and Biomedicine. The other Topic Editors declare no competing interests
Natural Killer (NK) cells have a unique role of detecting and destroying malignant and virus infected cells (Kiessling 1981) as a part of the immune system. The role of NK cells in the treatment of leukemia has been demonstrated in the context of hematopoietic stem cell transplantation (Ruggeri 2002, Ruggeri 2008). These findings support the use of allogeneic NK cells for treatment of patients and clinical responses have been observed (Miller 2005, Rubnitz 2010, Curti 2017, Dolstra 2017). Clinical-grade NK cell products can be generated by a growing variety of methods resulting in donor NK cells with different phenotype and function amendable to different clinical applications.
NK cell products made by different methods could be administered to a single patient with specific donor/recipient matching requirements, or the products could be manufactured in industrial-scale for universal “off-the-shelf” dispensation. These methods have different potential to scale from small phase I trials to treatment of hundreds of patients with an approved cell therapy product. NK cell products thus can cover the needs from individualized medicine to universal products.
Starting materials to generate clinical NK cell products include human whole blood, apheresis harvests, umbilical cord blood, NK cell lines, induced pluripotent stem cells and hematopoietic stem cells, with varying availability and protocol requirements, receptor repertoire and function.
Genetic modifications of immune cells have raised great interest for patient treatment due to high clinical response rates for patient T cells modified with chimeric antigen receptors. Serious side effects have been observed, prompting the clinical development of “safer” immune effector cells. Genetic modifications can generate NK cell products with novel functionality, including specificity of target cell recognition, signaling, reduced inhibition, improved survival or additional protein secretion. NK cells have a natural reactivity against viruses and thus have been described to be relatively resistant to genetic modification by viral particles. Methods have been developed to successfully modify NK cells or their progenitors.
Manufacturing of NK cell products for patients requires the use of appropriate reagents, disposables and environments to fulfill the needs for regulatory acceptance for clinical application. Closed systems can support manufacturing of NK cell products in a clean room at lower grades. They also require validation of the closed system.
Overall, a large range of methods to “produce” NK cells in high quantity and with high functionality has been developed, successfully translating basic research into GMP procedure and use in clinical trials.
This Research Topic reviews current methods to provide NK cells for treatment of patients, their phenotype and function and their uses in patient treatment. Individual methods are described in details and new approaches are proposed for further translation into GMP protocols.
Dr. Huppert is employed by Glycostem Therapeutics B.V. Dr. Leung is a part-time employee of Miltenyi Biotec and Biomedicine. The other Topic Editors declare no competing interests