Alectinib boosts anti-tumor efficacy of disialoganglioside 2 chimeric antigen receptor T cells in ALK-mutated neuroblastoma by suppressing programmed death-ligand 1
Menée in vitro et à l'aide d'une xénogreffe de neuroblastome avec mutation ALK, cette étude met en évidence un mécanisme par lequel l'alectinib, via la suppression du ligand PD-L1, améliore l'efficacité anti-tumorale des lymphocytes CAR-T ciblant le disialoganglioside 2
Background : High-risk ALK-mutant neuroblastoma (NB) presents challenges due to drug resistance and an immunosuppressive tumour microenvironment (TME). Combining molecular targeted therapy with adoptive cell therapy offers a potential therapeutic strategy.
Objective : To investigate the effects of alectinib, an ALK inhibitor, with disialoganglioside 2 (GD2) chimeric antigen receptor T (CAR-T) cell therapy in overcoming immune evasion in ALK-mutant NB.
Methods : Interferon gamma-induced programmed death-ligand 1 (PD-L1) expression and ALK signalling were analysed in ALK-mutant NB cells. The combination of alectinib and GD2 CAR-T cells was assessed in vitro, including sequential co-culture assays, and in vivo in an ALK-mutant xenograft model with multiple treatment arms.
Results : Alectinib suppressed PD-L1 expression by inhibiting ALK downstream pathways, including STAT3 and ERK1/2 phosphorylation. In vitro studies showed enhanced anti-tumour efficacy of GD2 CAR-T cells in combination with alectinib, with synergistic effect becoming evident in sequential coculture models. In vivo, the combination therapy reduced tumour growth, extended survival, and was associated with decreased PD-L1 expression and increased CAR-T cell infiltration.
Conclusion : Alectinib enhances the efficacy of GD2 CAR-T therapy in ALK-mutant NB primarily by attenuating PD-L1-mediated immune evasion, supporting its potential as a combinatorial therapeutic strategy.
British Journal of Cancer , article en libre accès, 2026