CELL INTELLIGENCE · 肿瘤细胞治疗研究

Despite advances in anti-disialoganglioside (GD2) immunotherapy, high-risk neuroblastoma (NB) remains a clinical challenge. Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity is a potent mechanism of action of anti-GD2 antibody. However, dose-intensive chemotherapy causes NK cell depletion. Here, a positive association between intratumoral NK cell infiltration and anti-GD2 efficacy was first observed in clinical samples. We then established the unique advantages of ex vivo expanded and activated umbilical cord blood (UCB)-derived NK cells in terms of cytotoxicity, persistence, exhaustion resistance, and safety from preclinical models to clinical cases compared with patient-derived PB NK cells. Anti-GD2 antibody further enhanced the superiority of UCB NK cells in terms of their functional status, persistence, and capacity to remodel an immune-activated tumor microenvironment. Combined treatment with UCB NK cells and an anti-GD2 led to synergistic effects in vitro and in mice and achieved complete and partial responses in two patients with relapsed/refractory NB, with no additive toxicity. Mechanistically, the anti-GD2 antibody induced a "high activating-low inhibitory" phenotype in UCB NK cells, and donor UCB NK cells showed dynamically lower levels of immune checkpoints but higher levels of memory-like markers than those of recipient NK cells when combined with anti-GD2 therapy. Collectively, this study is the first translational investigation of UCB NK cells combined with anti-GD2 therapy in NB, bridging preclinical mechanistic insights into an early clinical proof-of-concept. A phase I study of UCB NK cell infusion combined with anti-GD2 therapy in children with high-risk, relapsed/refractory NB is ongoing at our center (NCT06631391).