The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD<sub>2</sub> Antibody Dinutuximab Beta
Treatment of high-risk neuroblastoma (NB) patients with the anti-GD<sub>2</sub> antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/19/4842 |
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| author | Nikolai Siebert Justus Leopold Maxi Zumpe Sascha Troschke-Meurer Simon Biskupski Alexander Zikoridse Holger N. Lode |
| author_facet | Nikolai Siebert Justus Leopold Maxi Zumpe Sascha Troschke-Meurer Simon Biskupski Alexander Zikoridse Holger N. Lode |
| author_sort | Nikolai Siebert |
| collection | DOAJ |
| description | Treatment of high-risk neuroblastoma (NB) patients with the anti-GD<sub>2</sub> antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a therapeutic benefit but strongly induced Treg, we investigated here a DB-based immunotherapy combined with the immunocytokine FAP-IL-2v, which comprises a fibroblast activation protein α (FAP)-specific Ab linked to a mutated IL-2 variant (IL-2v) with abolished binding to the high-affinity IL-2 receptor, thus stimulating NK cells without induction of Treg. Effects of FAP-IL-2v on NK cells, Treg and ADCC mediated by DB, as well as FAP expression in NB, were investigated by flow cytometry, calcein-AM-based cytotoxicity assay and RT-PCR analysis. Moreover, the impact of soluble factors released from tumor cells on FAP expression by primary fibroblasts was assessed. Finally, a combined immunotherapy with DB and FAP-IL-2v was evaluated using a resistant syngeneic murine NB model. Incubation of leukocytes with FAP-IL-2v enhanced DB-specific ADCC without induction of Treg. FAP expression on NB cells and myeloid-derived suppressor cells (MDCS) in tumor tissue was identified. A tumor-cell-dependent enhancement in FAP expression by primary fibroblasts was demonstrated. Combination with DB and FAP-IL-2v resulted in reduced tumor growth and improved survival. Analysis of tumor tissue revealed increased NK and cytotoxic T cell numbers and reduced Treg compared to controls. Our data show that FAP-IL-2v is a potent immunocytokine that augments the efficacy of DB against NB, providing a promising alternative to IL-2. |
| first_indexed | 2024-03-09T21:55:48Z |
| format | Article |
| id | doaj.art-766250d45da64f159e30ce3628ba295f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:55:48Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-766250d45da64f159e30ce3628ba295f2023-11-23T19:57:31ZengMDPI AGCancers2072-66942022-10-011419484210.3390/cancers14194842The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD<sub>2</sub> Antibody Dinutuximab BetaNikolai Siebert0Justus Leopold1Maxi Zumpe2Sascha Troschke-Meurer3Simon Biskupski4Alexander Zikoridse5Holger N. Lode6Department of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, GermanyDepartment of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, GermanyTreatment of high-risk neuroblastoma (NB) patients with the anti-GD<sub>2</sub> antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a therapeutic benefit but strongly induced Treg, we investigated here a DB-based immunotherapy combined with the immunocytokine FAP-IL-2v, which comprises a fibroblast activation protein α (FAP)-specific Ab linked to a mutated IL-2 variant (IL-2v) with abolished binding to the high-affinity IL-2 receptor, thus stimulating NK cells without induction of Treg. Effects of FAP-IL-2v on NK cells, Treg and ADCC mediated by DB, as well as FAP expression in NB, were investigated by flow cytometry, calcein-AM-based cytotoxicity assay and RT-PCR analysis. Moreover, the impact of soluble factors released from tumor cells on FAP expression by primary fibroblasts was assessed. Finally, a combined immunotherapy with DB and FAP-IL-2v was evaluated using a resistant syngeneic murine NB model. Incubation of leukocytes with FAP-IL-2v enhanced DB-specific ADCC without induction of Treg. FAP expression on NB cells and myeloid-derived suppressor cells (MDCS) in tumor tissue was identified. A tumor-cell-dependent enhancement in FAP expression by primary fibroblasts was demonstrated. Combination with DB and FAP-IL-2v resulted in reduced tumor growth and improved survival. Analysis of tumor tissue revealed increased NK and cytotoxic T cell numbers and reduced Treg compared to controls. Our data show that FAP-IL-2v is a potent immunocytokine that augments the efficacy of DB against NB, providing a promising alternative to IL-2.https://www.mdpi.com/2072-6694/14/19/4842neuroblastomaimmunotherapydinutuximab betafibroblast activation protein αFAP-IL-2vmyeloid-derived suppressor cells |
| spellingShingle | Nikolai Siebert Justus Leopold Maxi Zumpe Sascha Troschke-Meurer Simon Biskupski Alexander Zikoridse Holger N. Lode The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD<sub>2</sub> Antibody Dinutuximab Beta Cancers neuroblastoma immunotherapy dinutuximab beta fibroblast activation protein α FAP-IL-2v myeloid-derived suppressor cells |
| title | The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD<sub>2</sub> Antibody Dinutuximab Beta |
| title_full | The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD<sub>2</sub> Antibody Dinutuximab Beta |
| title_fullStr | The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD<sub>2</sub> Antibody Dinutuximab Beta |
| title_full_unstemmed | The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD<sub>2</sub> Antibody Dinutuximab Beta |
| title_short | The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD<sub>2</sub> Antibody Dinutuximab Beta |
| title_sort | immunocytokine fap il 2v enhances anti neuroblastoma efficacy of the anti gd sub 2 sub antibody dinutuximab beta |
| topic | neuroblastoma immunotherapy dinutuximab beta fibroblast activation protein α FAP-IL-2v myeloid-derived suppressor cells |
| url | https://www.mdpi.com/2072-6694/14/19/4842 |
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