GD2-CART01 治疗复发/难治高危神经母细胞瘤。

GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma.

机构信息

From the Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy (F.D.B., B.D.A., I.C., G.D.B., M.A.D.I., A.S., A.M., M.G.C., D.P., M. Amicucci, G.L.P., V.B., M.S., S.D.C., M. Guercio, Z.A., L.I., M. Algeri, P.M., F.G., C.Q., F.L.), the Transfusion Unit, Department of Laboratories (G.L.), Officina Farmaceutica, Good Manufacturing Practice Facility (M. Gunetti, S.I., R.B., S.M.), and the Nuclear Medicine Unit (M.C.G., M.F.V.), Department of Imaging (G.S.C.), IRCCS Ospedale Pediatrico Bambino Gesù, and the Department of Life Sciences and Public Health, Catholic University of the Sacred Heart (F.L.), Rome, the Pediatric Hematology and Oncology Unit, IRCCS Policlinico San Matteo, Pavia (F.B.), the Pediatric Hematology-Oncology Unit, Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," Trieste (M.R.), Pediatric Oncology Hematology, Mother and Child Health Department, Santa Maria della Misericordia Hospital, Perugia (K.P.), the Pediatric Hematology-Oncology Unit, Ospedale dei Bambini, Azienda Socio Sanitaria Territoriale Spedali Civili Brescia, Brescia (V.F.), and the Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples (C.Q.) - all in Italy; and INSERM, Centre d'Investigation Clinique 1418 (CIC1418) Epidémiologie Clinique, Paris (R.A.).

出版信息

N Engl J Med. 2023 Apr 6;388(14):1284-1295. doi: 10.1056/NEJMoa2210859.

DOI:10.1056/NEJMoa2210859

PMID:37018492

Abstract

BACKGROUND

Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma.

METHODS

In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01).

RESULTS

A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×10 CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×10 CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively.

CONCLUSIONS

The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT03373097.).

摘要

背景

嵌合抗原受体（CAR）表达 T 细胞免疫疗法靶向肿瘤细胞表达的二唾液酸神经节苷脂 GD2，可能是高危神经母细胞瘤患者的一种治疗选择。

方法

在一项学术性的 1-2 期临床试验中，我们招募了患有复发性或难治性高危神经母细胞瘤的患者（年龄 1 至 25 岁），以测试表达诱导型半胱天冬酶 9 自杀基因的自体第三代 GD2-CAR T 细胞（GD2-CART01）。

结果

共有 27 名接受过多线预处理的神经母细胞瘤患儿（12 例难治性疾病，14 例复发性疾病，1 例一线治疗结束时完全缓解）入组并接受了 GD2-CART01 治疗。未观察到 GD2-CART01 生成失败。在试验的 1 期部分测试了 3 个剂量水平（每公斤体重 3×、6×和 10×10 个 CAR 阳性 T 细胞），未记录到剂量限制性毒性作用；试验 2 期的推荐剂量为每公斤体重 10×10 CAR 阳性 T 细胞。27 例患者中有 20 例（74%）发生细胞因子释放综合征，20 例中有 19 例（95%）为轻度。1 例患者激活了自杀基因，GD2-CART01 迅速消除。GD2 靶向 CAR T 细胞在体内扩增，27 例患者中有 26 例在输注后 30 个月内可在外周血中检测到（中位持续时间为 3 个月；范围为 1 至 30）。17 名患儿对治疗有反应（总反应率为 63%）；9 名患儿完全缓解，8 名患儿部分缓解。在接受推荐剂量的患者中，3 年总生存率和无事件生存率分别为 60%和 36%。