Novel anti-GD2 CAR-T cells exhibit superior cytotoxicity against neuroblastoma

Abstract

Treatment of high-risk paediatric neuroblastoma represents an unmet clinical need. Chimeric antigen receptor-modified T cell (CAR-T) therapy is a promising treatment option, but there exist some challenges regarding specificity and potency. The current study used ganglioside GD2 as a target for CAR-T construction because of its selective overexpression in neuroblastoma cells. We engineered a GD2-based CAR-T construct, including ICOS and 4-1BB co-stimulatory domains for better persistence. The cytotoxicity of the generated CAR-T cells (PG3-GD2-CAR-T) was verified using in vitro and in vivo assays. PG3-GD2-CAR-T cells exerted potent anti-tumour activity in vitro and in vivo, with minimal effects on peripheral blood cells. PG3-GD2-CAR-T cells exhibited encouraging specificity for and potency against neuroblastoma.

GD2-targeting therapy: a comparative analysis of approaches and promising directions

“…The ICOS domain (a member of the CD28 family) can also be added to the CAR construct to enhance the antitumor activity of CD8+ T cells by differentiating CD4+ T cells into the Th1/Th17 phenotype (284). In addition, the ICOS domain has a better effect on CAR-T survival compared to CD28 and also complements the function of the 4-1BB domain, including reducing tonic signaling (284), which likely contributed to the better persistence and antitumor activity of GD2 CAR-T cells in vivo (285). At the same time, combined stimulation of CD28 and 4-1BB may contribute to cytokine storm due to forced stimulation of CD28 (286).…”