A novel, non-feeder-cell approach to generate large numbers of Cytokine-Induced Memory-Like NK cells for adoptive cells therapies

Abstract

We have constructed two heterodimeric multi-cytokine fusions, HCW9201 and HCW9206, to support a “Kick and Expand” approach to activate and induce proliferation of purified NK cells for adoptive cell therapy (ACT). HCW9201 is a heterodimeric fusion protein complex comprising human IL-15 (complexed with an IL-15Rα-sushi domain), IL-18 and IL-12. HCW9206 is heterodimeric fusion protein comprising human IL-15 (complexed with an IL-15Rα-sushi domain), IL-7, and IL-21. When purified human NK cells from peripheral blood were activated with HCW9201 for three hours and then incubated with HCW9206 in combination with a capture antibody, the HCW9201-activated NK cells expanded approximately 100–300 folds within 14 days. The expanded NK cells exhibit a cytokine-induced memory-like (CIML) phenotype with a high metabolic rate and respiratory capacity, remarkable anti-tumor activity, and persistence when they were adoptively transferred into NSG mice. They also retained their heightened responsiveness when re-stimulated with tumor targets. Cytokine dependent epigenetic demethylation imprints of the Ifng promoter region were also observed for at least 10 days after the NK cells were adoptively transferred to NSG mice. In conclusion, a simple, scalable, non-feeder-cell-based “Kick and Expand” process was developed to support the generation of large numbers of CIML NK cells for multiple rounds of ACT using peripheral blood NK cell. We also provide data to show that these CIML NK cells are an excellent source for generation of CAR-NK cells.

Research progress of interleukin-15 in cancer immunotherapy

“…The latest study found similar results, saying HCW9218 could be safely administered systemically to reduce senescent cells and alleviate senescenceassociated secretory phenotype in mice. It indicates that HCW9218 represents a novel immunotherapy and a clinically promising new class of senotherapeutic agents targeting cellular senescence-associated diseases (Shrestha et al, 2023).…”

Natural killer cell-derived exosomes for cancer immunotherapy: innovative therapeutics art

“…Feeder cells also play an important role in the expansion of NK cells by providing cell-to-cell communication [ 61 ]. Although research continues to find new methods to reduce dependence on feeder cells and increase the efficiency of NK cell expansion, for example, the use of two heterodimeric multi-cytokine fusions for NK cell proliferation and activation [ 62 ].…”