Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma

Springer Science and Business Media LLC - Tập 64 - Trang 621-634 - 2015
Diana Seidel1,2, Anastasia Shibina3,2, Nikolai Siebert1, Winfried S. Wels4, C. Patrick Reynolds2, Nicole Huebener1,2,5, Holger N. Lode1
1Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
2Texas Tech University Health Sciences Cancer Center, Lubbock, USA
3Rhön Clinic Frankfurt/Oder, Internal Medicine, Frankfurt/Oder, Germany
4Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt a. M., Germany
5Max-Delbrück Center for Molecular Medicine, Berlin, Germany

Tóm tắt

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.

Tài liệu tham khảo

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