GD2-CART01 Elicits Clinical Activity, Tolerability in Pediatric R/R Neuroblastoma


The investigational CAR T-cell therapy GD2-CART01 showed preliminary antitumor activity and safety in pediatric patients with relapsed or refractory high-risk neuroblastoma, according to data from a phase 1/2 trial.

Oladapo O. Yeku, MD, PhD

Oladapo O. Yeku, MD, PhD

The investigational CAR T-cell therapy GD2-CART01 showed preliminary antitumor activity and safety in pediatric patients with relapsed or refractory high-risk neuroblastoma, according to data from a phase 1/2 trial (NCT03373097) published in the New England Journal of Medicine.1

Three-year results from the study showed that patients who received GD2-CART01 (n = 27) experienced an overall response rate of 63%, with 9 patients achieving a complete response (CR). Additionally, patients who received the recommended dose had a 3-year overall survival (OS) rate of 60% and a 3-year event-free survival (EFS) rate of 36%. Expansion of GD2-targeted CAR T cells was observed in vivo and were detectable in peripheral blood of nearly all patients (n = 26 of 27) up to 30 months post infusion, with a median persistence of 3 months (range, 1-30).

GD2-CART01 is specific for the disialoganglioside GD2, which is expressed in high levels on neuroblastoma cells. The agent incorporates CD28 and 4-1BB as costimulatory domains; all CAR T-cell therapies currently approved by the FDA for patients with hematologic malignancies contain at least 1 costimulatory domain. Investigators also designed GD2-CART01 with a safety switch by including the inducible DNA construct iC9 that encodes for capase 9, which disables or kills the CAR T cells when activated.1,2

“Expression of GD2 is low in healthy tissue and elevated in multiple tumor types, including neuroblastoma,” Oladapo O. Yeku, MD, PhD; and Dan L. Longo, MD, wrote in an editorial on the study.2 “This differential expression renders it a tumor-associated molecule; it has been successfully targeted in neuroblastoma with antibodies with no evidence of toxic effects, and an anti-GD2 antibody is currently a standard of care for this disease.”

The phase 1 portion of the trial enrolled patients with relapsed disease or who had had persistent or progressive disease during first-line treatment. Patients with metastatic disease and MYCN amplification were eligible for enrollment in phase 2 following the completion of frontline treatment, even if they had experienced a CR.1

The dose-finding phase 1 part of the study followed an escalation and de-escalation schema. Patients initially received GD2-CART01 at a dose of 3 × 106 CAR-positive T cells per kg of body weight. The specified dose escalation levels were 6 × 106 CAR-positive T cells per kg and 10 × 106 CAR-positive T cells per kg. If dose-limiting toxicities (DLTs) were associated with the initial dose, 2 × 106 CAR-positive T cells per kg and 1 × 106 CAR-positive T cells were planned as additional de-escalation dose levels.1

The primary end point was identifying DLTs in phase 1 and determining the antitumor effect of GD2-CART01 in phase 2. Secondary end points included in vivo persistence/expansion of infused CAR T cells, time to progression, EFS, OS, and the elimination of CAR T cell through iC9 in case of toxicity.3

A total of 27 patients with a median age of 6.7 years (range, 2.7-18.6) were enrolled to the study and underwent treatment with GD2-CART01. Prior to enrollment all patients had disease resistance to 2 or more prior lines of treatment (range, 2-6). Most patients had active, stage IV metastatic disease at screening before treatment (n = 26), including 6 individuals with bulky disease. All patients were enrolled at a single institution in Italy.1,3

Most patients were males (67%), had relapsed disease (52%), underwent prior treatment with an anti-GD2 monoclonal antibody (52%), and had an metaiodobenzylguanidine (MIBG) score of 7 or less before infusion (67%).

Regarding MYCN status, patients had amplification (26%), gain (19%), normal (37%), and unknown (19%). The median number of prior lines of treatment was 3 (range, 1-6).1

GD2-CART01 was successfully produced for all patients. The median number of CAR-positive T cells was 2 × 109 ± 1.4 × 109 cells per kg (range, 0.7-6.9 × 109). The median viability was 90.5% ± 3.7% (range, 82.2%-96.1%) and a median transduction efficiency of 72.4% ± 9.9% (range, 50.8%-87.3%). Multiple doses of CAR-positive T cell s were produced for each patient, with 11 patients receiving multiple infusions. Each patient could receive a maximum of 4 infusions.1

Safety results from the trial revealed that no DLTs occurred in phase 1 and the recommended dose of GD2-CART01 was determined to be 10 × 106 CAR-positive T cells per kg. The most common adverse events (AEs) of any grade included cytokine release syndrome (CRS) after the first infusion (74%), of which most instances were grade 1 or 2 (95%). Other grade 1 or 2 AEs included rash (n = 3), dysuria (n = 2), anemia (n = 8), thrombocytopenia (n = 1). One patient experienced a grade 3 infection, and 1 had a grade 4 brain hemorrhage.1

All patients experienced severe hematologic AEs; grade 3 AEs included anemia (n = 19) and thrombocytopenia (n = 4), with 27 patients experiencing grade 4 neutropenia and 19 experiencing grade 4 thrombocytopenia. Additionally, 7 patients developed transient hepatic toxic effects, 5 of whom had hepatic toxic effects present before enrollment or before GD2-CART01 infusion that transiently worsened with the development of CRS.

Additional findings from the study showed that, at a median follow-up of 1.7 years (IQR, 1.2-2.6), CR was maintained in 5 patients. All the patients who experienced a CR did so following the first infusion of GD2-CART01 and did not receive additional treatment.

In the overall cohort, the mean MIBG score decreased from a 13 (range, 0-72) to 8 (range, 0-38). The 3-year OS rate was 40% and the 3-year EFS rate was 27%. Patients who experienced a CR after the first infusion had a 3-year OS rate of 66% and a 3-year EFS rate of 50%.1

Notably, patients with low disease burden experienced significantly longer survival compared with those with a higher disease burden. The 3-year OS rate was 67% among patients with low disease burden compared with 0% for those with a high burden (P < .001). The 3-year EFS rates were 58% vs 0%, respectively (P < .001). High disease burden was defined as bulky disease, bone marrow infiltration of greater than 50%, or an MIBGSIOPEN score higher than 7.

Study authors concluded that their findings suggest that GD2-CART01 could lead to sustained eradication of disease in a proportion of patients with relapsed or refractory neuroblastoma. Additional studies are planned to further determine the role of GD2-CART01 in the treatment paradigm of neuroblastoma.1

"The extent to which the patients’ tumors maintained an immunosuppressive environment and whether this affected the efficacy of autologous GD2-CART01 is not known,” Yeku and Longo wrote.2 “A nuanced understanding of these and other potential mechanisms of treatment failure may set the stage for tailored and rationally designed combination therapies in the future.”


  1. Del Bufalo F, De Angelis B, Caruana I, et al; Precision Medicine Team–IRCCS Ospedale Pediatrico Bambino Gesù. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N Engl J Med. 2023;388(14):1284-1295. doi:10.1056/NEJMoa2210859
  2. Yeku OO, Longo DL. CAR T cells for neuroblastoma. N Engl J Med. 2023;388(14):1328-1331. doi:10.1056/NEJMe2300317
  3. Anti-GD2 CAR T cells in pediatric patients affected by high risk and/or relapsed/refractory neuroblastoma or other GD2-positive solid tumors. Updated March 24, 2022. Accessed April 27, 2023.
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