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Published on: February 8, 2022
Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma
Diana Seidel1, Anastasia Shibina, Nikolai Siebert
1Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Ferdinand-Sauerbruch Str., 17475, Greifswald, Germany.
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.
Insights
Engineered natural killer (NK) cells targeting disialoganglioside GD2 show promise for neuroblastoma (NB) treatment. These GD2-specific NK cells effectively kill drug-resistant NB cells and demonstrate anti-tumor activity in vivo.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Disialoganglioside GD2 is a key target for neuroblastoma (NB) immunotherapy.
- Current anti-GD2 antibody therapies show success but face challenges in high-risk NB cases.
- Novel approaches are needed to overcome treatment resistance in NB.
Purpose of the Study:
- To evaluate a genetically engineered natural killer (NK) cell line, NK-92-scFv(ch14.18)-zeta, for targeting GD2-positive neuroblastoma (NB).
- To assess the efficacy of these chimeric antigen receptor-expressing NK cells against drug-resistant NB cells in vitro and in vivo.
Main Methods:
- Genetic engineering of NK-92 cells to express a GD2-specific chimeric antigen receptor (CAR) derived from the ch14.18 antibody.
- In vitro assessment of NK-92-scFv(ch14.18)-zeta's ability to lyse GD2-positive NB cell lines, including multidrug-resistant variants.
- In vivo evaluation of NK-92-scFv(ch14.18)-zeta's anti-tumor response in a xenograft mouse model of drug-resistant GD2-positive NB.
Main Results:
- NK-92-scFv(ch14.18)-zeta effectively lysed GD2-positive NB cells, including partially and multidrug-resistant lines.
- GD2 recognition by the CAR was identified as the primary mechanism of lysis, independent of conventional NK cell receptor interactions.
- Significant anti-tumor activity was observed in vivo in a drug-resistant NB xenograft model.
Conclusions:
- GD2-specific CAR-engineered NK cells (NK-92-scFv(ch14.18)-zeta) demonstrate potent and specific anti-NB activity.
- This approach offers a promising alternative for treating challenging, drug-resistant neuroblastoma.
- NK-92-scFv(ch14.18)-zeta exhibits stability and activity, suggesting potential for clinical development.
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