Department of Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.
St Anna Children's Hospital and Children's Cancer Research Institute, Department of Studies and Statistics for Integrated Research and Projects, Medical University of Vienna, Vienna, Austria.
J Clin Oncol. 2023 Jun 10;41(17):3135-3148. doi: 10.1200/JCO.22.01630. Epub 2023 Feb 28.
Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB.
Patients age 1-21 years underwent T-/B-cell-depleted haplo-SCT followed by DB and scIL2. The primary end point 'success of treatment' encompassed patients receiving six cycles, being alive 180 days after end of trial treatment without progressive disease, unacceptable toxicity, acute graft-versus-host-disease (GvHD) ≥grade 3, or extensive chronic GvHD.
Seventy patients were screened, and 68 were eligible for immunotherapy. Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1-6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42; = .026). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred.
DB therapy after haplo-SCT in patients with rHR-NB is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells.
复发高危神经母细胞瘤（rHR-NB）患者预后不良。我们假设通过利用自然杀伤细胞的细胞毒性功能和抗 GD2 抗体 dinutuximab beta（DB）对其进行激活，可以通过移植半相合干细胞（haplo-SCT）来引发针对神经母细胞瘤的移植物抗神经母细胞瘤效应。本研究旨在评估 rHR-NB 患者在接受haplo-SCT 后使用 DB 联合皮下白细胞介素-2（scIL2）免疫治疗的安全性、可行性和结果。
年龄在 1-21 岁的患者接受 T-/B 细胞耗竭性haplo-SCT 后，接受 DB 和 scIL2 治疗。主要终点“治疗成功”包括接受 6 个周期治疗、在试验治疗结束后 180 天无疾病进展、不可接受的毒性、急性移植物抗宿主病（GvHD）≥3 级或广泛慢性 GvHD 的患者。
70 名患者接受了筛选，68 名患者符合免疫治疗条件。DB 周期的中位数为 6 个（范围为 1-9 个）。scIL2 周期的中位数为 3 个（1-6 个）。37 名患者（54.4%）达到了主要终点。中位观察时间为 7.8 年。从开始试验治疗起，5 年无事件生存率（EFS）和总生存率分别为 43%（95%CI，31-55）和 53%（95%CI，41-65）。免疫治疗前完全缓解（CR；52%；95%CI，31-69）或部分缓解（44%；95%CI，27-60）患者的 5 年 EFS 显著高于无反应/混合反应/进展性疾病患者（13%；95%CI，1-42； =.026）。在 43 名haplo-SCT 后有疾病证据的患者中，整体反应率为 51%（22 名患者），其中 15 名患者达到 CR（35%）。两名患者出现 2 级和 3 级 GvHD。未发生意外不良事件。
rHR-NB 患者在接受 haplo-SCT 后使用 DB 治疗是可行的，发生 GvHD 的风险低，并且可能由于供体来源的效应细胞增强了抗神经母细胞瘤活性而导致长期缓解。
