Neuroblastoma (NB) is the most common extracranial solid
tumor in children. Combining passive immunotherapy with an antibody to the disialoganglioside GD2 (
ch14.18/SP2/0) and
cytokines with
13-cis-retinoic acid for post-myeloablative maintenance
therapy increased survival in high-risk NB, but the overall prognosis for these children is still in need of improvement.
Fenretinide (4-HPR) is a synthetic
retinoid that has shown clinical activity in recurrent NB and is cytotoxic to a variety of
cancer cells, in part via the accumulation of dihydroceramides, which are precursors of GD2. We investigated the effect of
4-HPR on CHO-derived, ch14.18-mediated anti-NB effector functions,
complement-dependent cytotoxicity (CDC), and antibody-dependent and antibody-independent cellular cytotoxicity (ADCC and AICC, respectively). Here, we demonstrate for the first time that pretreatment of
fenretinide-resistant NB cells with
4-HPR significantly enhanced
ch14.18/CHO-mediated CDC and ADCC and AICC by both human natural killer cells and peripheral blood mononuclear cells. Treatment with
4-HPR increased GD2 and
death receptor (DR) expression in resistant NB cells and induced an enhanced
granzyme B and
perforin production by effector cells. Blocking of
ganglioside synthesis with a
glucosylceramide synthase inhibitor abrogated the increased ADCC response but had no effect on the AICC, indicating that GD2 induced by
4-HPR mediates the sensitization of NB cells for ADCC. We also showed that
4-HPR induced increased GD2 and DR expression in a resistant NB xenograft model that was associated with an increased ADCC and AICC response using explanted
tumor target cells from 4-HPR-treated mice. In summary, these findings provide an important baseline for the combination of
4-HPR and passive immunotherapy with
ch14.18/CHO in future clinical trials for high-risk NB patients.