From Bambino Gesù Children’s Hospital in Rome comes a report that a third-generation CAR T cell therapy targeting GD2, designated GD2–CART01, induced durable remissions and long-term survival in children with high-risk metastatic, relapsed, or refractory neuroblastoma.
High-risk neuroblastoma often carries poor long-term outcomes after first-line failure, with prior work noting progression-free survival and overall survival largely under 20%.
Recent results from the Society of Pediatric Oncology European Neuroblastoma Group’s randomized BEACON-Neuroblastoma trial reported improved outcomes, as compared to historical controls, but the overall response rate did not exceed 30%, and a high rate of subsequent progression and relapse was observed.
Evidence from the Children’s Oncology Group ANBL1221 trial and subsequent North American and European analyses reported a 41.5% overall response rate and 67.9% one-year progression-free survival for chemoimmunotherapy using GD2-directed monoclonal antibodies with chemotherapy. Among 21 responders who stopped therapy, subsequent one-year progression-free survival was 26%.
In the study, “GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/2 trial,” published in Nature Medicine, researchers conducted a single-center Phase I/IIa clinical trial to assess safety, maximum tolerated dose, overall response rate and complete remission at six weeks, three months and six months, with secondary endpoints including five-year overall survival and GD2–CART01 persistence.
A dose-finding stage tested multiple concentrations using an escalation–deescalation design, followed by a Phase II stage treating all participants with the best performer. Primary goals included safety, identification of the maximum tolerated dose, overall response rate, and the dosage achieving complete remission at six weeks, three months, and six months. Secondary goals included five-year overall survival and persistence of GD2-CART01.
Among 32 evaluable children in the trial, overall response reached 66% (21/32). Complete remission reached 37% at six weeks, 34% at three months, and 40% at six months. GD2–CART01 persisted for at least 12 months in 64% of trial participants evaluable at longer follow-up.
With a median follow-up of 4.2 years, five-year overall survival for the trial cohort reached 42.67%.
Across the predefined target population with low disease burden, overall response reached 77%. Five-year overall survival reached 67.6%, and event-free survival reached 52.8%.
Better five-year overall and event-free survival rates were observed in children treated after one to two prior lines of therapy compared with those treated after three or more lines.
Cytokine release syndrome, an inflammatory reaction, occurred in 79.6% of treated children, mostly grades 1–2, with four grade 3 events.
Immune effector cell-associated neurotoxicity syndrome, a serious neurological and cognitive impairment, occurred in 10 children, reached grade 3 in four, and was controlled by rapidly activating the “safety switch,” an inducible caspase-9 suicide gene engineered into the infused GD2–CART01 cells. Activation occurred after rimiducid administration, with a rapid drop in circulating CAR T cells with clinical improvement reported.
Authors conclude that GD2–CART01 can induce sustained remissions in children with high-risk neuroblastoma, especially when administered at low disease burden and earlier in the treatment course. Next steps include a multicenter international Phase II clinical trial.
Written for you by our author Justin Jackson, edited by Sadie Harley, —this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive.
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More information:
Franco Locatelli et al, GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/2 trial, Nature Medicine (2025). DOI: 10.1038/s41591-025-03874-6
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