肿瘤细胞治疗研究
英文原题：Quadruple immunotherapy with allogeneic natural killer cell infusion for recurrent neuroblastoma.
四联免疫治疗对复发性神经母细胞瘤似乎可行且有效，不良反应可耐受。
背景/目的：尽管接受多模式治疗，复发/难治性（R/R）神经母细胞瘤仍具有致死性。我们评估了一种四联免疫治疗方案，包括单倍体相合自然杀伤（NK）细胞输注、dinutuximab beta、细胞因子和螺内酯；螺内酯可通过激动视黄醇X受体γ增强NK细胞细胞毒性。 方法：在这项单臂临床试验中，R/R神经母细胞瘤患儿接受化疗（环磷酰胺/托泊替康）、dinutuximab beta、螺内酯、低剂量白细胞介素2和粒细胞-巨噬细胞集落刺激因子，并输注单倍体相合NK细胞。每4–8周重复一个周期，直至完全缓解或未见客观应答。主要终点为应答率。不良事件按《常见不良事件术语标准》5.0版分级。纵向分析NK细胞比例和细胞毒性。 结果：共实施26个四联免疫治疗周期（每例1–10个周期），每周期NK细胞剂量为每千克受者体重12.4–42×10^6个细胞。治疗获得3例完全缓解、1例部分缓解和1例轻微缓解；两例骨髓受累患者均达到疾病清除。所有治疗周期后均发生3级血细胞减少，并伴发热；中性粒细胞减少中位持续时间为24.2天（范围13–42天）。细胞因子释放综合征较轻，未发生神经毒性。所有治疗相关毒性在下一疗程前均恢复至1级。没有患者因毒性停治。NK细胞输注后，外周血NK细胞比例可重复地在第21天达到峰值；同时，在抗GD2抗体存在时，这些细胞可有效杀伤IMR-32神经母细胞瘤靶细胞。1年无进展生存率和总生存率分别为60%和100%。 结论：四联免疫治疗用于复发性神经母细胞瘤似乎可行且有效，不良反应可耐受。仍需研究巩固治疗，以进一步提高缓解持久性。
BACKGROUND AIMS: Relapsed/refractory (R/R) neuroblastoma remains lethal despite multi-modality therapy. We evaluated a quadruple immunotherapy regimen combining haploidentical natural killer (NK) cell infusion, dinutuximab beta, cytokines and spironolactone, which enhances NK cytotoxicity via retinoid X receptor gamma agonism. METHODS: In this single-arm clinical trial, children with R/R neuroblastoma received chemotherapy (cyclophosphamide/topotecan), dinutuximab beta, spironolactone, low-dose interleukin 2 and granulocyte-macrophage colony-stimulating factor along with haploidentical NK cell infusion. Cycles were repeated every 4-8 weeks until complete remission or no objective response. The primary endpoint was response rate. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. NK cell frequency and cytotoxicity were profiled serially. RESULTS: A total of 26 cycles of quadruple immunotherapy were administered (one to 10 per patient), with the NK cell dose of each cycle ranging from 12.4 to 42 10 6 cells/kg recipient weight. Three complete responses, one partial response and one minor response were achieved; both patients with bone marrow involvement cleared the disease. Grade 3 cytopenia occurred after all cycles, accompanied by fever; median neutropenia duration was 24.2 days (range, 13-42 days). Cytokine release syndrome was mild; no neurotoxicity occurred. All treatment-related toxicities resolved to grade 1 before the next course. No patient discontinued therapy because of toxicity. After NK cell infusion, blood NK cell frequencies reproducibly peaked on day 21, coinciding with effective in vitro killing of IMR-32 neuroblastoma targets in the presence of anti-GD2 antibody. The 1-year progression-free survival and overall survival rates were 60% and 100%, respectively. CONCLUSIONS: Quadruple immunotherapy appeared feasible and effective for recurrent neuroblastoma with tolerable adverse effects. Future investigation regarding consolidation therapy is warranted to further improve remission durability.
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