title: Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma.
abstract: The disialoganglioside GD2 is a well-established target antigen for passive immunotherapy in neuroblastoma (NB). Despite the recent success of passive immunotherapy with the anti-GD2 antibody ch14.18 and cytokines, treatment of high-risk NB remains challenging. We expanded the approach of GD2-specific, antibody-based immunotherapy to an application of a GD2-specific natural killer (NK) cell line, NK-92-scFv(ch14.18)-zeta. NK-92-scFv(ch14.18)-zeta is genetically engineered to express a GD2-specific chimeric antigen receptor generated from ch14.18. Here, we show that chimeric receptor expression enables NK-92-scFv(ch14.18)-zeta to effectively lyse GD2(+) NB cells also including partially or multidrug-resistant lines. Our data suggest that recognition of GD2 by the chimeric receptor is the primary mechanism involved in NK-92-scFv(ch14.18)-zeta-mediated lysis and is independent of activating NK cell receptor/ligand interactions. Furthermore, we demonstrate that NK-92-scFv(ch14.18)-zeta is able to mediate a significant anti-tumor response in vivo in a drug-resistant GD2(+) NB xenograft mouse model. NK-92-scFv(ch14.18)-zeta is an NB-specific NK cell line that has potential for future clinical development due to its high stability and activity toward GD2(+) NB cell lines.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Ferdinand-Sauerbruch Str., 17475, Greifswald, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Seidel
authors.forename: Anastasia
authors.initials: A
authors.lastname: Shibina
authors.forename: Nikolai
authors.initials: N
authors.lastname: Siebert
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Nicole
authors.initials: N
authors.lastname: Huebener
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005732:Gangliosides / Q000235:genetics / Q000276:immunology*; D005818:Genetic Engineering; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D011946:Receptors, Antigen / Q000096:biosynthesis / Q000276:immunology; D057127:Single-Chain Antibodies / Q000276:immunology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D005732:Gangliosides; D011946:Receptors, Antigen; D057127:Single-Chain Antibodies; C025447:sialogangliosides; C019403:ganglioside, GD2