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Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy.

ABSTRACT: Neuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system which accounts for 8% of childhood cancers. Most NBs express high levels of the disialoganglioside GD2. Several antibodies have been developed to target GD2 on NB, including the human/mouse chimeric antibody ch14.18, known as dinutuximab. Dinutuximab used in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and isotretinoin (13-cis-retinoic acid) has a US Food and Drug Administration (FDA)-registered indication for treating high-risk NB patients who achieved at least a partial response to prior first-line multi-agent, multimodality therapy. The FDA registration resulted from a prospective randomized trial assessing the benefit of adding dinutuximab + cytokines to post-myeloablative maintenance therapy for high-risk NB. Dinutuximab has also shown promising antitumor activity when combined with temozolomide and irinotecan in treating NB progressive disease. Clinical activity of dinutuximab and other GD2-targeted therapies relies on the presence of the GD2 antigen on NB cells. Some NBs have been reported as GD2 low or negative, and such tumor cells could be nonresponsive to anti-GD2 therapy. As dinutuximab relies on complement and effector cells to mediate NB killing, factors affecting those components of patient response may also decrease dinutuximab effectiveness. This review summarizes the development of GD2 antibody-targeted therapy, the use of dinutuximab in both up-front and salvage therapy for high-risk NB, and the potential mechanisms of resistance to dinutuximab.

SUBMITTER: Keyel ME

PROVIDER: S-EPMC6306059 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy.

Keyel Michelle E ME Reynolds C Patrick CP

Biologics : targets & therapy 20181221

Neuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system which accounts for 8% of childhood cancers. Most NBs express high levels of the disialoganglioside GD2. Several antibodies have been developed to target GD2 on NB, including the human/mouse chimeric antibody ch14.18, known as dinutuximab. Dinutuximab used in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and isotretinoin (13-<i>cis-</i>retinoic acid) has a US Food and Drug Administration ...[more]

PMID: 30613134

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Project description:Simple Summary We investigated the effects of chemotherapeutics used for the frontline treatment of newly diagnosed high-risk neuroblastoma patients in combination with anti-GD2 antibody ch14.18/CHO (dinutuximab beta, DB) in the presence of immune cells in preclinical models of neuroblastoma. The combined treatment showed an up-to-17-fold-stronger and GD2-specific cytotoxic effect compared to the controls treated with chemotherapy alone in the presence or absence of immune cells. These findings further support a clinical evaluation of DB in combination with frontline induction therapy for high-risk neuroblastoma patients. Abstract 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.

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Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy.

Publications

Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy.

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