Clinical Phenotype and Management of Severe Neurotoxicity Observed in Patients with Neuroblastoma Treated with Dinutuximab Beta in Clinical Trials

Wieczorek, Aleksandra; Manzitti, Carla; Garaventa, Alberto; Gray, Juliet; Papadakis, Vassilios; Valteau‐Couanet, Dominique; Zachwieja, Katarzyna; Pötschger, Ulrike; Pribill, Ingrid; Fiedler, Stefan; Ladenstein, Ruth; Lode, Holger N.

doi:10.3390/cancers14081919

Cited by 9 publications

(7 citation statements)

References 30 publications

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“…Monoclonal antibodies like Dintuximab beta are supposed not to penetrate the healthy blood–brain barrier (BBB). When drug levels of Db in cerebrospinal fluid were determined in three patients with acute neurotoxic side effects of the immunotherapy, no relevant levels were measured [ 26 ]. Actually, relapse after Db immunotherapy occurred in both of our patients intracranial.…”

Section: Discussionmentioning

confidence: 99%

Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3

Eichholz,

Heubach,

Arendt

et al. 2024

Cancer Immunol Immunother

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Background GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. Methods The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. Results We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. Conclusion Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

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Section: Discussionmentioning

confidence: 99%

Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3

Eichholz,

Heubach,

Arendt

et al. 2024

Cancer Immunol Immunother

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“…In addition, we observed no severe neurological disturbances—mydriasis and visual disturbances were reversible and did not require discontinuation of therapy. Although rare, severe neurological AEs have been reported to occur in patients treated with dinutuximab beta [ 33 ]. Patients should therefore be strictly observed by experienced healthcare professionals who can react immediately to any clinical or laboratory changes to prevent the development of more severe and potentially irreversible conditions.…”

Section: Discussionmentioning

confidence: 99%

Dinutuximab Beta Maintenance Therapy in Patients with High-Risk Neuroblastoma in First-Line and Refractory/Relapsed Settings—Real-World Data

Wieczorek,

Żebrowska,

Ussowicz

et al. 2023

JCM

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Dinutuximab beta is approved for the maintenance treatment of patients with high-risk neuroblastoma (HR-NB), including patients with relapsed/refractory (R/R) disease. However, the data on its use in real-world clinical practice is limited. We retrospectively reviewed the clinical records of 54 patients with HR-NB who received maintenance therapy with dinutuximab beta in first-line (37 patients) or R/R settings (17 patients) at three centers in Poland. Of the 37 patients who received first-line treatment, twenty-eight had a complete response, two had a partial response, three had progressive disease, and four relapsed at the end of treatment. The median overall survival (OS) was 24.37 months, and the three-year progression-free survival (PFS) and OS were 0.63 and 0.80, respectively. Of the 17 patients in the R/R group, 11 had a complete response, two had a partial response, one had stable disease, and three had progressive disease or relapsed at the end of treatment. The median OS was 33.1 months and the three-year PFS and OS were 0.75 and 0.86, respectively. Treatment was generally well tolerated, including in patients with co-morbidities and those who had experienced toxicities with previous therapies. These findings demonstrate that the use of dinutuximab beta is feasible and beneficial as a first-line or R/R treatment in routine clinical practice in Poland.

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“…Subsequent SIOPEN clinical trials of a combination of dinutuximab beta with/without subcutaneous administration of IL2, isotretinoin, and standard chemotherapy regimens showed improved 5-year survival. However, due to side effects and lack of benefit, IL2 is not recommended for further use (101)(102)(103).…”

Section: Function Of Disialoganglioside Gd2 and Its Role In Oncogenesismentioning

confidence: 99%

GD2-targeting therapy: a comparative analysis of approaches and promising directions

Philippova,

Shevchenko,

Sennikov

2024

Front. Immunol.

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Disialoganglioside GD2 is a promising target for immunotherapy with expression primarily restricted to neuroectodermal and epithelial tumor cells. Although its role in the maintenance and repair of neural tissue is well-established, its functions during normal organism development remain understudied. Meanwhile, studies have shown that GD2 plays an important role in tumorigenesis. Its functions include proliferation, invasion, motility, and metastasis, and its high expression and ability to transform the tumor microenvironment may be associated with a malignant phenotype. Structurally, GD2 is a glycosphingolipid that is stably expressed on the surface of tumor cells, making it a suitable candidate for targeting by antibodies or chimeric antigen receptors. Based on mouse monoclonal antibodies, chimeric and humanized antibodies and their combinations with cytokines, toxins, drugs, radionuclides, nanoparticles as well as chimeric antigen receptor have been developed. Furthermore, vaccines and photoimmunotherapy are being used to treat GD2-positive tumors, and GD2 aptamers can be used for targeting. In the field of cell therapy, allogeneic immunocompetent cells are also being utilized to enhance GD2 therapy. Efforts are currently being made to optimize the chimeric antigen receptor by modifying its design or by transducing not only αβ T cells, but also γδ T cells, NK cells, NKT cells, and macrophages. In addition, immunotherapy can combine both diagnostic and therapeutic methods, allowing for early detection of disease and minimal residual disease. This review discusses each immunotherapy method and strategy, its advantages and disadvantages, and highlights future directions for GD2 therapy.

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Clinical Phenotype and Management of Severe Neurotoxicity Observed in Patients with Neuroblastoma Treated with Dinutuximab Beta in Clinical Trials

Cited by 9 publications

References 30 publications

Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3

Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3

Dinutuximab Beta Maintenance Therapy in Patients with High-Risk Neuroblastoma in First-Line and Refractory/Relapsed Settings—Real-World Data

GD2-targeting therapy: a comparative analysis of approaches and promising directions

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