Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment

Abstract

Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor–ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.

The biological role and immunotherapy of gangliosides and GD3 synthase in cancers

“…In addition, dinutuximab beta markedly improved NK-cell cytokine secretion, degranulation, and cytotoxicity. Collectively, the combination of haplo HSCT and dinutuximab beta for the treatment of stage IV relapsed neuroblastoma was feasible ( Seitz et al, 2021 ). Cheung et al reported that in a phase 2 clinical trial ( ClinicalTrials.gov NCT00911560) one hundred two patients with HR-NB and a history of Parkinson’s disease (PD) received treatment with the GD2/GD3 vaccine plus β-glucan.…”

Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma

“…OS at 2 and 3 years was 68.6% and 58%, respectively, and EFS at 2 and 3 years was 51.2% and 46.9%, respectively (median follow-up 2.5 years) [21]. Thus, the combinatorial therapy of haplo-SCT and dinutuximab beta seem to increase the efficacy of immunotherapy [22].…”

Strategies for Potentiating NK-Mediated Neuroblastoma Surveillance in Autologous or HLA-Haploidentical Hematopoietic Stem Cell Transplants

“…Having demonstrated the safety of haplo-HSCT, this technique has been combined with the infusion of chimeric anti-GD2 mAbs and IL-2 in children with relapsed HR-NB [ 86 ]. The immune monitoring of this cohort of patients provided some very relevant information.…”