Although the development of cancer immunotherapeutics is now flourishing, the list of targets of approved agents has been short and limited to protein molecules. The approval of Dinutuximab, a chimeric anti-GD2 antibody, for the treatment of high-risk neuroblastoma in 2015 marks the first new agent targeting a glycolipid molecule, thereby widening the net of potential pharmaceutical targets. This was largely based on the pioneer work of Dr. Yu and her leadership during the entire course of ch14.18 development, from preclinical studies through the randomized COG phase III clinical trial. The latter showed a significant improvement in the 2-year event-free survival (66 ± 5% versus 46 ± 5%, p = 0.01) and overall survival (86 ± 4% versus 75 ± 5%, p = 0.02) for patients randomized to immunotherapy. A long term follow up (median 9.97 years) of the randomized trial continued to show significant survival benefits of immunotherapy over standard therapy, although differences in survival was smaller due to late relapses. Subsequently, ch14.18 produced in CHO cells (Dinutuximab-beta) showed similar efficacy for high-risk neuroblastoma in a randomized SIOPEN study whether IL2 was added or not. This led to the approval of Dinutuximab-beta in 2017 in EU.

To improve the efficacy of dinutuximab, combination of dinutuximab with salvage chemotherapy was investigated in patients with relapsed/refractory neuroblastoma. Treatment with Irinotecan–temozolomide–dinutuximab-GMCSF was well-tolerated and induced objective responses in 22/53 patients (41·5%). These findings provided the rationales for the ongoing development of a COG phase III study of combining dinutuximab with induction chemotherapy in high-risk neuroblastoma. In addition, combination of dinutuximab with DFMO, anti-PD1 or anti-CD47 showed synergistic anti-tumor efficacy in preclinical studies. Combination with DFMO upregulated the ligands for NK stimulatory molecule NKG2D, while combination with anti-PD-1 induced immunogenic cell death and T cell immunity. Blockade of CD47, which conveys ‘Don’t eat me’ signal to macrophages, provides potent synergy with anti-GD2. Ligation of GD2 on tumor cells causes upregulation of surface calreticulin, a pro-phagocytic ‘Eat me’ signal that primes cells for removal and interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7.

The success of immunotherapy targeting the GD2 antigen with dinutuximab has fueled the interest in developing next generation GD2-targeting immunotherapeutics. These include humanized anti-GD2 antibodies, one of which, naxitamab, has received FDA approval for the treatment of relapsed neuroblastoma in November 2020. Additional strategies include cytokine-fused GD2-specific antibodies, GD2-specific chimeric antigen receptor T/NKT cells, GD2 vaccine, anti-GD2 idiotype monoclonal antibody, and anti-O-acetyl GD2 antibody. Advance in these active or passive cancer immunotherapies hold promises to further improve the outcome of neuroblastoma.