The Glycosphingolipid GD2 as an Effective but Enigmatic Target of Passive Immunotherapy in Children with Aggressive Neuroblastoma (HR-NBL)

Neuroblastoma (NBL), the most frequent and lethal pediatric cancer of children in pre-school age, is still considered enigmatic. This is in view of its extreme heterogeneity, from spontaneous regression to incurable disease (in a larger proportion of cases, approx. 40%). NBL has an embryonal origin, not completely understood. This origin was recently discussed in view of new findings on Schwann precursor cells. Furthermore, a very complex and heterogeneous genomic landscape has so far hampered the success with so-called targeted or precision-medicine strategies. Since over three decades, the glycosphingolipid or disialoganglioside GD2 was shown to be expressed on NBL cells and utilized as target for passive immunotherapy with anti-GD2 antibodies (GD2-IMT). In 2010, a new international protocol has been established with GD2-IMT, which increases remission length and survival in aggressive NBL (HR-NBL). By reviewing the different biological and molecular aspects of NBL and GD2-IMT, this mini-review questions some of today’s accepted interpretations and particularly the present lack of association between GD2-IMT and the underlying molecular landscape. An alternative model is presented involving the Micro-Foci inducing virus (MFV) that we have studied for several years. MFV infection can induce extensive genomic aberrations (such as 100X NMYC DNA-amplification). Since this family of viruses uses molecules for cell adhesion and entry similar to GD2 (i.e., GM2), it is here hypothesized that GD2 is the port-of-entry for MFV and that the great success of anti-GD2 therapies is partly/completely explained by inhibition of spreading of this clastogenic virus in aggressive NBL.