In the haploidentical allogeneic SCT (alloSCT) setting, ch14.18 is used to take advantage of more potent donor-derived NK cells, which are predominant in the early posttransplant period while T cells recover only after a delayed period of time. To date, a variety of anti-GD2 mAbs have been investigated in the clinical setting, and ch14.18/CHO (dinutuximab beta), a human/mouse chimeric mAb, has been approved for the treatment of HR-NB and is currently used as first-line treatment after HD-CT and autoSCT. This requires adequate multidrug analgesia to prevent neuropathic pain - the main side effect. GD2 is also expressed in healthy human tissues, but is primarily limited to neurons, peripheral sensory nerve fibers and skin melanocytes. Moreover, these mAbs can activate the classical complement system pathway to elicit complement-dependent cytotoxicity (CDC). Anti-GD2 mAbs target the tumor-associated antigen (TAA) disialoganglioside GD2 on neuroblastoma cells, mediating ADCC via the Fc domain, which is mainly recognized by natural killer (NK) cells. Targeted immunotherapy with monoclonal antibodies (mAbs) has shown significant results in the treatment of patients. The established therapeutic approach for HR-NB consists of multimodal approaches including surgical resection of the primary tumor, induction chemotherapy, high-dose chemotherapy (HD-CT) followed by autologous stem cell transplantation (autoSCT), and radiotherapy as maintenance therapy. High-risk neuroblastoma (HR-NB) and especially refractory or relapsed (R/R) disease still represent a therapeutic challenge, displaying poor cure rates with standard protocols, reporting a 3- and 5-year event-free survival (EFS) of 6–50%. Its prognosis depends on the stage, patient age, molecular characteristics, and response to standard therapy. Neuroblastoma (NB) is the most common childhood extracranial solid tumor. Consequently, we propose an adjusted administration of both antibody constructs, considering the state of posttransplant immune recovery, to optimize anti-tumor activity. Our study highlights the importance of analyzing effector cell subsets in patients before initiating antibody-based therapy. Using patient PBMCs taken at different time points posttransplant, significant lysis with both constructs was detectable depending on percentages and total numbers of T and NK cells in the early posttransplant phase, NK cells were predominant and ch14.18 was superior, whereas later on, T cells represented the majority of immune cells and NG-CU was more effective. At a ratio of 1:1, ch14.18 was more effective than NG-CU. To decipher the influence of effector cell subsets on lysis, different ratios of T and NK cells were tested. NG-CU showed enhanced cytotoxicity compared to ch14.18, even at lower concentrations and E: T ratios, and completely eradicated LS cells after 72 h. Mean specific lysis of LS cells utilizing PBMCs from healthy donors and ch14.18 (1 µg/ml) was 40/66/75% after 12/24/48 h compared to 66/93/100% in the presence of NG-CU (100 ng/ml). Different antibody concentrations and effector-to-target ratios ( E:T) were evaluated using xCELLigence RTCA system, peripheral blood mononuclear cells (PBMCs) (healthy donors and patients after alloSCT), and neuroblastoma cell lines (LS/LAN-1). We investigated whether T cell-recruiting bispecific anti-CD3/GD2 antibody NG-CU might be an alternative to therapeutic anti-GD2 monoclonal antibody (mAb) ch14.18, mediating complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) through natural killer (NK) cells for immunotherapy in high-risk/relapsed neuroblastoma after autologous/allogeneic stem cell transplantation (auto/alloSCT).
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