title: Ex vivo activation of CD56(+) immune cells that eradicate neuroblastoma.
abstract: Despite the use of intensive contemporary multimodal therapy, the overall survival of patients with high-risk neuroblastoma is still less than 50%. Therefore, immunotherapy without cross-resistance and overlapping toxicity has been proposed. In this study, we report the development of a novel strategy to specifically activate and expand human CD56(+) (NCAM1) natural killer (NK) immune cells from normal donors and patients with neuroblastoma. Enriched CD56(+) cells from peripheral blood were mixed with CD56(-) fraction at 1:1 ratio and cultured in the presence of OKT3, interleukin (IL)-2, and -15 for five days and then without OKT3 for 16 more days. The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B. Successful clinical scale-up in a good manufacturing practices (GMP)-compliant bioreactor yielded effector cells that in a neuroblastoma xenograft model slowed tumor growth and extended survival without GVHD. Investigation of CD56(+) cells from patients with neuroblastoma revealed a similar postactivation phenotype and lytic activity. Our findings establish a novel and clinically expedient strategy to generate allogeneic or autologous CD56(+) cells that are highly cytotoxic against neuroblastoma with minimal risk of GVHD.
authors: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Piya
authors: P
authors: Rujkijyanont
authors: Wing Keung
authors: WK
authors: Chan
authors: Paul W
authors: PW
authors: Eldridge
authors: Timothy
authors: T
authors: Lockey
authors: Martha
authors: M
authors: Holladay
authors: Barbara
authors: B
authors: Rooney
authors: Andrew M
authors: AM
authors: Davidoff
authors: Wing
authors: W
authors: Leung
authors: Queenie
authors: Q
authors: Vong
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism*; D018929:Cell Culture Techniques / Q000592:standards; D015550:Cell Degranulation / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D006087:Graft vs Host Reaction / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D055607:Receptors, Natural Killer Cell / Q000276:immunology / Q000378:metabolism; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D019002:CD56 Antigen; D055607:Receptors, Natural Killer Cell