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: Diana Seidel, Anastasia Shibina, Nikolai Siebert, Winfried S Wels, C Patrick Reynolds, Nicole Huebener, Holger N Lode
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 64 Issue 5 Pg. 621-34 (May 2015) ISSN: 1432-0851 [Electronic] Germany
• PMID: 25711293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Anti-Idiotypic
• Gangliosides
• Receptors, Antigen
• Single-Chain Antibodies
• sialogangliosides
• ganglioside, GD2

Topics

• Animals
• Antibodies, Anti-Idiotypic (immunology)
• Cell Line
• Cytotoxicity, Immunologic (immunology)
• Drug Resistance, Neoplasm
• Female
• Gangliosides (genetics, immunology)
• Genetic Engineering
• Humans
• Immunotherapy, Adoptive (methods)
• Killer Cells, Natural (immunology)
• Mice
• Mice, Inbred NOD
• Neoplasm Transplantation
• Neuroblastoma (immunology, therapy)
• Receptors, Antigen (biosynthesis, immunology)
• Single-Chain Antibodies (immunology)