Antidisialoganglioside (GD2), third-generation chimeric antigen receptor (CAR) T cells (GD2–CART01) have shown encouraging efficacy in children with high-risk metastatic, relapsed, or refractory neuroblastoma in the interim analysis of a phase 1/2 clinical trial. We now present the final results obtained in all 35 patients enrolled and in 19 additional children selected with the same criteria of the trial and treated in a hospital exemption setting. Primary endpoints for the trial were safety, maximum tolerated dose, overall response rate (ORR) and complete remission rate at various timepoints. Secondary endpoints included 5-year overall survival (OS) and persistence of GD2–CART01. No new safety signals were observed. Grade 3 immune effector cell-associated neurotoxicity syndrome was diagnosed in four children and rapidly controlled with the activation of the inducible caspase-9 suicide gene by rimiducid. The maximum tolerated dose was 10 × 106CAR+ cells per kg. The ORR of the patients enrolled in the clinical trial was 66% (21/32—excluding the three patients treated in nonevidence of disease). The complete remission rate at 6 weeks, 3 months and 6 months reached 37%, 34% and 40%, respectively. GD2–CART01 persisted ≥12 months in 64% of the patients enrolled in the clinical trial. With a median follow-up of 4.2 years, the 5-year OS for the trial cohort was 42.67%. In total, 38 of 54 children were treated with low disease burden at 10 × 106 GD2–CART01 cells per kg (defined as the target population), including eight patients consolidated in nonevidence of disease after the first line. The ORR in the target population was 77%, the 5-year OS and event-free survivals were 68% and 53%, respectively. Substantially superior 5-year OS and event-free survivals were observed in patients treated after one or two lines of therapy versus those treated after ≥3 lines of therapy. Better results were observed in patients whose lymphocyte collection was performed at the time of diagnosis. These results confirm that GD2–CART01 can induce durable remissions in children with high-risk metastatic, relapsed, or refractory neuroblastoma. ClinicalTrials.gov identifier: NCT03373097.
Locatelli, F., Pagliara, D., De Ioris, M. A., Becilli, M., Del Baldo, G., Serra, A., Mastronuzzi, A., Cefalo, M. G., Li Pira, G., Leone, G., Bertaina, V., Fabozzi, F., Di Nardo, M., Rosignoli, C., D'Andrea, M. L., Crocoli, A., Vennarini, S., Sinibaldi, M., Di Cecca, S., Guercio, M., Iaffaldano, L., Lucarelli, B., Algeri, M., Merli, P., Colafati, G. S., De Angelis, B., Quintarelli, C., Del Bufalo, F., GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/2 trial, <<NATURE MEDICINE>>, 2025; 31 (11): 3689-3699. [doi:10.1038/s41591-025-03874-6] [https://hdl.handle.net/10807/329486]
GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/2 trial
Locatelli, Franco;Mastronuzzi, Angela;
2025
Abstract
Antidisialoganglioside (GD2), third-generation chimeric antigen receptor (CAR) T cells (GD2–CART01) have shown encouraging efficacy in children with high-risk metastatic, relapsed, or refractory neuroblastoma in the interim analysis of a phase 1/2 clinical trial. We now present the final results obtained in all 35 patients enrolled and in 19 additional children selected with the same criteria of the trial and treated in a hospital exemption setting. Primary endpoints for the trial were safety, maximum tolerated dose, overall response rate (ORR) and complete remission rate at various timepoints. Secondary endpoints included 5-year overall survival (OS) and persistence of GD2–CART01. No new safety signals were observed. Grade 3 immune effector cell-associated neurotoxicity syndrome was diagnosed in four children and rapidly controlled with the activation of the inducible caspase-9 suicide gene by rimiducid. The maximum tolerated dose was 10 × 106CAR+ cells per kg. The ORR of the patients enrolled in the clinical trial was 66% (21/32—excluding the three patients treated in nonevidence of disease). The complete remission rate at 6 weeks, 3 months and 6 months reached 37%, 34% and 40%, respectively. GD2–CART01 persisted ≥12 months in 64% of the patients enrolled in the clinical trial. With a median follow-up of 4.2 years, the 5-year OS for the trial cohort was 42.67%. In total, 38 of 54 children were treated with low disease burden at 10 × 106 GD2–CART01 cells per kg (defined as the target population), including eight patients consolidated in nonevidence of disease after the first line. The ORR in the target population was 77%, the 5-year OS and event-free survivals were 68% and 53%, respectively. Substantially superior 5-year OS and event-free survivals were observed in patients treated after one or two lines of therapy versus those treated after ≥3 lines of therapy. Better results were observed in patients whose lymphocyte collection was performed at the time of diagnosis. These results confirm that GD2–CART01 can induce durable remissions in children with high-risk metastatic, relapsed, or refractory neuroblastoma. ClinicalTrials.gov identifier: NCT03373097.
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