Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice
Background Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated b...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001560.full |
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| author | Jianping Sun Larry Wang Michael John Zobel Abigail K Zamora Hong-wei Wu Danny Lascano Jemily Malvar Michael A Sheard Robert C Seeger Eugene S Kim |
| author_facet | Jianping Sun Larry Wang Michael John Zobel Abigail K Zamora Hong-wei Wu Danny Lascano Jemily Malvar Michael A Sheard Robert C Seeger Eugene S Kim |
| author_sort | Jianping Sun |
| collection | DOAJ |
| description | Background Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival.Methods In vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints.Results In vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection.Conclusion Dinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB. |
| format | Article |
| id | doaj-art-bfe8dc20ceaf4f77a6534d0a408d1595 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-bfe8dc20ceaf4f77a6534d0a408d15952024-11-09T22:15:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001560Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in miceJianping Sun0Larry Wang1Michael John Zobel2Abigail K Zamora3Hong-wei Wu4Danny Lascano5Jemily Malvar6Michael A Sheard7Robert C Seeger8Eugene S Kim92 Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California, USA3 Department of Pathology and Laboratory Medicine, Children`s Hospital Los Angeles, Los Angeles, California, USA1 Division of Pediatric Surgery, Department of Surgery, Children’s Hospital Los Angeles, Los Angeles, California, USA1 Division of Pediatric Surgery, Department of Surgery, Children’s Hospital Los Angeles, Los Angeles, California, USA2 Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California, USA1 Division of Pediatric Surgery, Department of Surgery, Children’s Hospital Los Angeles, Los Angeles, California, USA2 Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California, USA2 Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California, USA2 Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California, USA1 Division of Pediatric Surgery, Department of Surgery, Children’s Hospital Los Angeles, Los Angeles, California, USABackground Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival.Methods In vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints.Results In vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection.Conclusion Dinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB.https://jitc.bmj.com/content/8/2/e001560.full |
| spellingShingle | Jianping Sun Larry Wang Michael John Zobel Abigail K Zamora Hong-wei Wu Danny Lascano Jemily Malvar Michael A Sheard Robert C Seeger Eugene S Kim Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice Journal for ImmunoTherapy of Cancer |
| title | Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice |
| title_full | Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice |
| title_fullStr | Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice |
| title_full_unstemmed | Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice |
| title_short | Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice |
| title_sort | initiation of immunotherapy with activated natural killer cells and anti gd2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice |
| url | https://jitc.bmj.com/content/8/2/e001560.full |
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