Anti-GD2 Directed Immunotherapy for High-Risk and Metastatic Neuroblastoma

Abstract

Neuroblastoma is one of the few childhood cancers that carries a tumor-specific antigen in the form of a glycolipid antigen known as GD2. It has restricted expression in normal tissue, such as peripheral afferent nerves. Monoclonal antibodies targeting GD2 have been applied clinically to high-risk neuroblastoma with significant success. However, there are different anti-GD2 products and administration regimens. For example, anti-GD2 has been used in combination with chemotherapy during the induction phase or with retinoic acid during the maintenance stage. Regimens also vary in the choice of whether to add cytokines (i.e., IL-2, GMCSF, or both). Furthermore, the addition of an immune enhancer, such as β-glucan, or allogeneic natural killer cells also becomes a confounder in the interpretation. The question concerning which product or method of administration is superior remains to be determined. So far, most studies agree that adding anti-GD2 to the conventional treatment protocol can achieve better short- to intermediate-term event-free and overall survival, but the long-term efficacy remains to be verified. How to improve its efficacy is another challenge. Late relapse and central nervous system metastasis have emerged as new problems. The methods to overcome the mechanisms related to immune evasion or resistance to immunotherapy represent new challenges to be resolved. The newer anti-GD2 strategies, such as bispecific antibody linking of anti-GD2 with activated T cells or chimeric antigen receptor T cells, are currently under clinical trials, and they may become promising alternatives. The use of anti-GD2/GD3 tumor vaccine is a novel and potential approach to minimizing late relapse. How to induce GD2 expression from tumor cells using the epigenetic approach is a hot topic nowadays. We expect that anti-GD2 treatment can serve as a model for the use of monoclonal antibody immunotherapy against cancers in the future.

Development of a reporter gene assay for antibody dependent cellular cytotoxicity activity determination of anti‐rabies virus glycoprotein antibodies

“…Studies have shown that vaccineinduced antibodies, and/or therapeutic mAbs could induce ADCC against CNS cancers both in vitro and in vivo. [31][32][33][34] In particular, anti-GD2 antibodies with major antineuroblastoma mechanisms of ADCC, [35][36][37] could improve the cure rate of metastatic CNS neuroblastoma 38 and have been applied effectively to high-risk neuroblastoma. For RABV, it has been reported that the protective activity of a particular RABV mAb in vivo did not correlate with its virusneutralizing activity in vitro, 39 indicating that Fc effector functions may contribute to protection effectiveness.…”

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

“…In the presence of human effector cells, including peripheral blood nuclear cells and granulocytes from healthy human donors, dinutuximab beta was found to mediate the lysis of human NB and melanoma cell lines in a dose-dependent manner (Fig. 1 ) [ 15 , 16 ].

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“…(4) Monoclonal antibodies such as anti-GD2 can induce calreticulin (‘eat me’ molecule) expression on neuroblastoma cells and enhance phagocytosis by macrophages. The figure was created using Biorender.com, and was adapted from Chan and Chan [ 16 ]. CDC complement-dependent cytotoxicity, NK natural killer, ADCC antibody-dependent cellular cytotoxicity, ADP antibody-dependent phagocytosis …”

Stimulation of natural killer cells with small molecule inhibitors of CD38 for the treatment of neuroblastoma

“…3,4 In high-risk NB patients, anti-GD2 mAbs such as naxitamab induce antibody-dependent cellmediated cytotoxicity (ADCC). However, the overall success of anti-GD2 mAb immunotherapy for NB is highly dependent on the antitumor activity of natural killer (NK) and other effector cells, 5,6 and failure to respond to treatment can be attributed to NB cell resistance 7 or the inability of effector cells to kill tumor cells. 8,9 As a result, the long-term efficacy of anti-GD2 mAb immunotherapy is unveried, and there is a pressing need for novel strategies to overcome resistance.…”

“…8,9 As a result, the long-term efficacy of anti-GD2 mAb immunotherapy is unveried, and there is a pressing need for novel strategies to overcome resistance. 7 It has been established that high-risk NB patients with increased RNA signatures for activated NK cells and CD8 + T cells experience improved outcomes. 10 This implies that agents that prevent down regulation of immune function in the tumor microenvironment could represent a strategy for overcoming resistance to immunotherapy in NB and other cancers.…”