Randomized use of anti-GD<sub>2</sub> antibody dinutuximab beta (DB) long-term infusion with and without subcutaneous interleukin-2 (scIL-2) in high-risk neuroblastoma patients with relapsed and refractory disease: Results from the SIOPEN LTI-trial.

Lode, Holger N.; Valteau‐Couanet, Dominique; Gray, Juliet; Luksch, Roberto; Wieczorek, Aleksandra; Castel, Victoria; Ash, Susan; Laureys, Geneviève; Papadakis, Vassilios; Owens, Cormac; Garaventa, Alberto; Manzitti, Carla; Siebert, Nikolai; Troschke-Meurer, Sascha; Glogova, Evgenia; Pötschger, Ulrike; Ladenstein, Ruth

doi:10.1200/jco.2019.37.15_suppl.10014

Cited by 14 publications

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“…Dinutuximab was approved for the treatment of high-risk neuroblastoma in the setting of minimal residual disease (42) and recently in neuroblastoma patients with refractory/resistant disease (43). However, dinutuximab is associated with doselimiting neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

O-Acetyl-GD2 as a Therapeutic Target for Breast Cancer Stem Cells

et al. 2022

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SynopsisA sugar-lipid molecule called OAcGD2 is a novel marker for breast cancer stem cells. Treatment with anti-OAcGD2 mAb8B6 may have superior anticancer efficacy by targeting cancer stem cells, thereby reducing metastasis and recurrence of cancer.BackgroundCancer stem cells (CSCs) that drive tumor progression and disease recurrence are rare subsets of tumor cells. CSCs are relatively resistant to conventional chemotherapy and radiotherapy. Eradication of CSCs is thus essential to achieve durable responses. GD2 was reported to be a CSC marker in human triple-negative breast cancer, and anti-GD2 immunotherapy showed reduced tumor growth in cell lines. Using a specific anti-OAcGD2 antibody, mAb8D6, we set out to determine whether OAcGD2+ cells exhibit stem cell properties and mAb8D6 can inhibit tumor growth by targeting OAcGD2+CSCs.MethodOAcGD2 expression in patient-derived xenografts (PDXs) of breast cancer was determined by flow cytometric analyses using mAb8D6. The stemness of OAcGD2+ cells isolated by sorting and the effects of mAb8B6 were assessed by CSC growth and mammosphere formation in vitro and tumor growth in vivo using PDX models.ResultWe found that the OAcGD2 expression levels in six PDXs of various molecular subtypes of breast cancer highly correlated with their previously defined CSC markers in these PDXs. The sorted OAcGD2+ cells displayed a greater capacity for mammosphere formation in vitro and tumor initiation in vivo than OAcGD2− cells. In addition, the majority of OAcGD2+ cells were aldehyde dehydrogenase (ALDH+) or CD44hiCD24lo, the known CSC markers in breast cancer. Treatment of PDXs-bearing mice with mAb8B6, but not doxorubicin, suppressed the tumor growth, along with reduced CSCs as assessed by CSC markers and in vivo tumorigenicity. In vitro, mAb8B6 suppressed proliferation and mammosphere formation and induced apoptosis of OAcGD2+ breast cancer cells harvested from PDXs, in a dose-dependent manner. Finally, administration of mAb8B6 in vivo dramatically suppressed tumor growth of OAcGD2+ breast CSCs (BCSCs) with complete tumor abrogation in 3/6 mice.ConclusionOAcGD2 is a novel marker for CSC in various subtypes of breast cancer. Anti-OAcGD2 mAb8B6 directly eradicated OAcGD2+ cells and reduced tumor growth in PDX model. Our data demonstrate the potential of mAb8B6 as a promising immunotherapeutic agent to target BCSCs.

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Section: Discussionmentioning

confidence: 99%

O-Acetyl-GD2 as a Therapeutic Target for Breast Cancer Stem Cells

et al. 2022

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“…Despite therapeutic advances, HRNB has a poor prognosis. Clinical trials led by the SIOPEN group have shown that immunotherapy with dinutuximab beta as part of multimodal treatment improves survival in patients with HRNB [ 8 , 9 , 12 , 13 ]. However, published literature on the use of this therapy in real-world settings is limited.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the positive results of the SIOPEN trials [ 8 , 12 , 13 ], dinutuximab beta was approved in Europe in May 2017 for the treatment of HRNB in patients ≥12 months of age who have achieved at least a partial response to induction chemotherapy, followed by MAT and ASCT, and in patients with a history of relapsed or refractory neuroblastoma with or without residual disease [ 14 ]. Five cycles of dinutuximab beta should be administered either as continuous infusion for the first 10 days of each 35-day cycle (10 mg/m 2 per day; cumulative dose 100 mg/m 2 ) or as short 8-h infusion for the first 5 days of the cycle (20 mg/m 2 per day; cumulative dose 100 mg/m 2 ) [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Dinutuximab Beta in Children with High-Risk Neuroblastoma: Experience from a Single Center in Croatia

et al. 2022

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To determine the potential benefits and feasibility of administering maintenance therapy with dinutuximab beta for high-risk neuroblastoma (HRNB) in clinical practice, a retrospective review of charts of patients with HRNB treated at a single center in Croatia (2012–2021) was undertaken. Of 23 patients with HRNB, 11 received up to five cycles of dinutuximab beta as part of multimodal therapy; 12 patients did not (i.e., no immunotherapy). In the no immunotherapy group, one patient had complete remission (8%), and 11 patients died of tumor progression (92%). In the dinutuximab beta group, eight patients had complete remission (73%; median duration of response 5 years and 2 months), one had stable disease (9%), and two died of disease (18%). Patients who received dinutuximab beta had a higher median event-free survival (40.0 months [range: 12.5–83.0]) and median overall survival (56.0 months [range: 16.2–101.0]) than those who did not (12.9 months [range: 3.3–126.0] and 20.7 months [3.3–126.0], respectively). Dinutuximab beta was generally well tolerated; adverse events were manageable and as reported in clinical studies. These results confirm the benefits and feasibility of maintenance therapy with dinutuximab beta as part of multimodal therapy for patients with HRNB in real-world clinical practice.

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“…As an on-target effect, pain, including neuropathic pain, is commonly experienced in children treated with dinutuximab beta [10][11][12]15]. GD2, the target of dinutuximab beta, is not only expressed on the surface of NB cells but also in normal human tissue in the central and peripheral nervous system [16].…”

Section: Painmentioning

confidence: 99%

“…Due to the immunotoxic effects of monoclonal antibodies [ 18 ], hypersensitivity reactions are an expected AE in patients receiving dinutuximab beta [ 10 , 11 , 15 ]. Hypersensitivity reactions may include mild symptoms (e.g.…”

Section: Optimising Supportive Care For Children Receiving Dinutuximab Betamentioning

confidence: 99%

Managing Adverse Events Associated with Dinutuximab Beta Treatment in Patients with High-Risk Neuroblastoma: Practical Guidance

et al. 2021

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Neuroblastoma is the most common extracranial solid tumour in children, accounting for 15% of all paediatric cancer deaths. High-risk neuroblastoma is a particularly challenging-to-treat form of disease that requires multimodality treatment, consisting of chemotherapy, surgery, high-dose chemotherapy with autologous haematopoietic stem cell rescue, radiotherapy and differentiation therapy. However, despite intense multimodal treatment regimens, the prognosis for this patient population remains poor. In recent years, immunotherapy with anti-disialoganglioside 2 (anti-GD2) antibodies was found to improve survival rates for patients with high-risk neuroblastoma. Based on studies led by the SIOPEN (International Society of Paediatric Oncology European Neuroblastoma) group, the anti-GD2 antibody dinutuximab beta was approved for use in high-risk neuroblastoma by the European Medicines Agency and has been implemented into the standard of care in many countries across Europe. However, immunotherapy with dinutuximab beta is associated with a number of adverse events that may be challenging for clinicians, such as pain, fever, hypersensitivity reactions and capillary leak syndrome. While these adverse events are considered manageable, there are currently no formal guidelines to support clinicians with their management. The aim of this article is to discuss the management of the most common adverse events encountered in clinical practice and to provide practical guidance to assist clinicians in minimising toxicity associated with dinutuximab beta. Key PointsDinutuximab beta can cause adverse events that warrant consideration and management.Most common adverse events include pain, fever, allergy and capillary leak syndrome.Practical guidance is provided on the management of the most common adverse events.

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Randomized use of anti-GD₂ antibody dinutuximab beta (DB) long-term infusion with and without subcutaneous interleukin-2 (scIL-2) in high-risk neuroblastoma patients with relapsed and refractory disease: Results from the SIOPEN LTI-trial.

Cited by 14 publications

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O-Acetyl-GD2 as a Therapeutic Target for Breast Cancer Stem Cells

O-Acetyl-GD2 as a Therapeutic Target for Breast Cancer Stem Cells

Dinutuximab Beta in Children with High-Risk Neuroblastoma: Experience from a Single Center in Croatia

Managing Adverse Events Associated with Dinutuximab Beta Treatment in Patients with High-Risk Neuroblastoma: Practical Guidance

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Randomized use of anti-GD2 antibody dinutuximab beta (DB) long-term infusion with and without subcutaneous interleukin-2 (scIL-2) in high-risk neuroblastoma patients with relapsed and refractory disease: Results from the SIOPEN LTI-trial.

Cited by 14 publications

References 0 publications

O-Acetyl-GD2 as a Therapeutic Target for Breast Cancer Stem Cells

O-Acetyl-GD2 as a Therapeutic Target for Breast Cancer Stem Cells

Dinutuximab Beta in Children with High-Risk Neuroblastoma: Experience from a Single Center in Croatia

Managing Adverse Events Associated with Dinutuximab Beta Treatment in Patients with High-Risk Neuroblastoma: Practical Guidance

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Product

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Randomized use of anti-GD₂ antibody dinutuximab beta (DB) long-term infusion with and without subcutaneous interleukin-2 (scIL-2) in high-risk neuroblastoma patients with relapsed and refractory disease: Results from the SIOPEN LTI-trial.