Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models
Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carbopla...
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MDPI AG
2023-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/3/904 |
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| author | Sascha Troschke-Meurer Maxi Zumpe Lena Meißner Nikolai Siebert Piotr Grabarczyk Hannes Forkel Claudia Maletzki Sander Bekeschus Holger N. Lode |
| author_facet | Sascha Troschke-Meurer Maxi Zumpe Lena Meißner Nikolai Siebert Piotr Grabarczyk Hannes Forkel Claudia Maletzki Sander Bekeschus Holger N. Lode |
| author_sort | Sascha Troschke-Meurer |
| collection | DOAJ |
| description | Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The effects on stress ligand and checkpoint expression by neuroblastoma cells and on activation receptors of NK cells were determined by using flow cytometry. NK-cell activity was measured with a CD107a/IFN-γ assay. Long-term cytotoxicity was analyzed in three spheroid models derived from GD2-positive neuroblastoma cell lines (LAN-1, CHLA 20, and CHLA 136) expressing a fluorescent near-infrared protein. Chemotherapeutics combined with DB in the presence of immune cells improved cytotoxic efficacy up to 17-fold compared to in the controls, and the effect was GD2-specific. The activating stress and inhibitory checkpoint ligands on neuroblastoma cells were upregulated by the chemotherapeutics up to 9- and 5-fold, respectively, and activation receptors on NK cells were not affected. The CD107a/IFN-γ assay revealed no additional activation of NK cells by the chemotherapeutics. The synergistic effect of DB with chemotherapeutics seems primarily attributed to the combined toxicity of antibody-dependent cellular cytotoxicity and chemotherapy, which supports further clinical evaluation in frontline induction therapy. |
| first_indexed | 2024-03-11T09:50:30Z |
| format | Article |
| id | doaj.art-dac5eb8557eb43c0a0bc068c0235c1a5 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:50:30Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-dac5eb8557eb43c0a0bc068c0235c1a52023-11-16T16:18:53ZengMDPI AGCancers2072-66942023-01-0115390410.3390/cancers15030904Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid ModelsSascha Troschke-Meurer0Maxi Zumpe1Lena Meißner2Nikolai Siebert3Piotr Grabarczyk4Hannes Forkel5Claudia Maletzki6Sander Bekeschus7Holger N. Lode8Department of Pediatric Oncology and Hematology, University Medicine Greifswald, Ferdinand-Sauerbruch Strasse 1, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, Ferdinand-Sauerbruch Strasse 1, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, Ferdinand-Sauerbruch Strasse 1, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, Ferdinand-Sauerbruch Strasse 1, 17475 Greifswald, GermanyDepartment of Internal Medicine, Clinic III—Hematology, Oncology, University Medicine Greifswald, Ferdinand-Sauerbruch Strasse 1, 17475 Greifswald, GermanyDepartment of Internal Medicine, Clinic III—Hematology, Oncology, University Medicine Greifswald, Ferdinand-Sauerbruch Strasse 1, 17475 Greifswald, GermanyDepartment of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, GermanyZIK Plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, Ferdinand-Sauerbruch Strasse 1, 17475 Greifswald, GermanyAnti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The effects on stress ligand and checkpoint expression by neuroblastoma cells and on activation receptors of NK cells were determined by using flow cytometry. NK-cell activity was measured with a CD107a/IFN-γ assay. Long-term cytotoxicity was analyzed in three spheroid models derived from GD2-positive neuroblastoma cell lines (LAN-1, CHLA 20, and CHLA 136) expressing a fluorescent near-infrared protein. Chemotherapeutics combined with DB in the presence of immune cells improved cytotoxic efficacy up to 17-fold compared to in the controls, and the effect was GD2-specific. The activating stress and inhibitory checkpoint ligands on neuroblastoma cells were upregulated by the chemotherapeutics up to 9- and 5-fold, respectively, and activation receptors on NK cells were not affected. The CD107a/IFN-γ assay revealed no additional activation of NK cells by the chemotherapeutics. The synergistic effect of DB with chemotherapeutics seems primarily attributed to the combined toxicity of antibody-dependent cellular cytotoxicity and chemotherapy, which supports further clinical evaluation in frontline induction therapy.https://www.mdpi.com/2072-6694/15/3/904ADCCcarboplatinchemoimmunotherapycisplatincyclophosphamidedinutuximab beta |
| spellingShingle | Sascha Troschke-Meurer Maxi Zumpe Lena Meißner Nikolai Siebert Piotr Grabarczyk Hannes Forkel Claudia Maletzki Sander Bekeschus Holger N. Lode Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models Cancers ADCC carboplatin chemoimmunotherapy cisplatin cyclophosphamide dinutuximab beta |
| title | Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models |
| title_full | Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models |
| title_fullStr | Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models |
| title_full_unstemmed | Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models |
| title_short | Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models |
| title_sort | chemotherapeutics used for high risk neuroblastoma therapy improve the efficacy of anti gd2 antibody dinutuximab beta in preclinical spheroid models |
| topic | ADCC carboplatin chemoimmunotherapy cisplatin cyclophosphamide dinutuximab beta |
| url | https://www.mdpi.com/2072-6694/15/3/904 |
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