Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma

Abstract

BACKGROUND Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte–macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P = 0.01) and overall survival (86±4% vs. 75±5% at 2 years, P = 0.02 without adjustment for interim analyses). CONCLUSIONS Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma.

Fenretinide sensitizes multidrug-resistant human neuroblastoma cells to antibody-independent and ch14.18-mediated NK cell cytotoxicity

“…Recently, it has been reported that the addition of the anti-GD2 antibody ch14.18/SP2/0, combined with rIL-2 and GM-CSF, to standard therapy provides a clinical benefit with a 20% improvement in the 2-year prevention of relapse for children with high-risk neuroblastoma [52]. The primary mechanism of action of the anti-GD2 antibody is the induction of ADCC.…”

“…The GD2-specific chimeric antibody ch14.18 generated in SP2/0 hybridoma cells Overall survival at two years was 86% for the immunotherapy group versus 75% for the standard treatment group (p= 0.016) [52]. It has been shown for the first time that the inclusion of immunotherapy in standard therapy provides a clinical benefit with improved event-free and overall survival for children with high-risk neuroblastoma, highlighting the role of immunotherapy in treatment of this challenging disease.…”

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

“…The only clinically available mAbs in neuroblastoma cells is dinutuximab, a chimeric, human-murine, anti-disialoganglioside GD2 overexpressed on NB tumors. Dinutuximab was approved in combination with granulocyte/monocyte-colony stimulating factor (GM-CSF), aldesleukin (interleukin-2 [IL-2]), and isotretinoin (13-cis-retinoic acid [RA]) for maintenance treatment of patients with high-risk neuroblastoma who respond at least to firstline multimodality therapy [10]. In phase III trials, dinutuximab increased 2-year event-free survival (EFS) and overall survival (OS) compared to standard treatment.…”

“…Their homing in tumor microenvironment site and production of vEGF contribute to metastasis [42]. In aggressive NMA neuroblastoma, it was shown that TAMs are correlated to bad prognosis [10]. Macrophages are key players in maintaining the tissue homeostasis, shaping adaptive immune response, inflammation, and tissue repair [44].…”

Targeted therapy in pediatric and adolescent oncology

“…5). 36 A study gathering further information to support a licensing application is in progress. Recent reanalysis of a German study nonrandomly assigning patients to ch14.18 after high-dose therapy supports its efficacy.…”