The
ganglioside GD2 is an important target in childhood
cancer. Nevertheless, the only
therapy targeting GD2 that is approved to date is the
monoclonal antibody dinutuximab, which is used in the
therapy of
neuroblastoma. The relevance of GD2 as a target in other
tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric
tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline
glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the
antigen.
Ewing's sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity.
Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells.
Dinutuximab beta in combination with
irinotecan and
temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial
metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked
ganglioside synthesis via
eliglustat, since
dinutuximab cannot cross the blood-brain barrier.
Eliglustat is an inhibitor of
glucosylceramide synthase, and it is used for treating children with
Gaucher's disease.
Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that
dinutuximab might be effective in
tumors with high GD2 expression. Moreover, disrupting the
ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal
cancer.