Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent medulloblastoma and ependymoma
Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent medulloblastoma and ependymoma
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DOI：
10.1093/neuonc/noaa047
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发表时间：
2020-08-01
期刊：
影响因子：
15.9
通讯作者：
Gopalakrishnan, Vidya
中科院分区：
文献类型：
--
作者：
Khatua, Soumen;Cooper, Laurence J. N.;Gopalakrishnan, Vidya
背景。复发性儿童髓母细胞瘤和室管膜瘤预后严峻。我们报告了一项在这些肿瘤中体外扩增的自体自然杀伤 (NK) 细胞脑室内输注的首次人体 I 期研究以及相关研究。方法。 12 名患者入组，其中 9 名接受方案治疗，每周最多 3 次输注，剂量从 3 x 10(6) 逐渐增加到 3 x 10(8) NK 细胞/m(2)/输注，最多 3 个周期。获取脑脊液 (CSF) 用于 NK 细胞的细胞特征、持久性和表型分析。对 7 名患者进行了治疗前 MRI 扫描的放射组学表征，以开发基于非侵入性成像的特征。结果。所有 9 名患者均实现了 112 次脑室内输注 NK 细胞的 NK 细胞收获、扩增、释放和安全性的主要目标。没有剂量限制性毒性。除 1 名患者在研究随访结束时疾病稳定 1 个月外，所有患者均显示疾病进展 (PD)。另一名患者在 5 次 NK 细胞输注后出现短暂放射学反应，随后进展为 PD。在较高剂量水平下，重复输注治疗期间脑脊液中的 NK 细胞数量增加（平均 11.6 倍）。频繁输注 NK 细胞会导致脑脊液细胞增多。对 7 名患者的放射组学特征进行了分析，评估了预测前期放射学变化的能力，尽管它们没有达到统计学显着性。结论。本研究证明了自体 NK 细胞脑室内输注的生产可行性和安全性。这些发现支持对脑恶性肿瘤儿童局部区域 NK 细胞输注的进一步研究。
Background. Recurrent pediatric medulloblastoma and ependymoma have a grim prognosis. We report a first-in-human, phase I study of intraventricular infusions of ex vivo expanded autologous natural killer (NK) cells in these tumors, with correlative studies.Methods. Twelve patients were enrolled, 9 received protocol therapy up to 3 infusions weekly, in escalating doses from 3 x 10(6) to 3 x 10(8) NK cells/m(2)/infusion, for up to 3 cycles. Cerebrospinal fluid (CSF) was obtained for cellular profile, persistence, and phenotypic analysis of NK cells. Radiomic characterization on pretreatment MRI scans was performed in 7 patients, to develop a non-invasive imaging-based signature.Results. Primary objectives of NK cell harvest, expansion, release, and safety of 112 intraventricular infusions of NK cells were achieved in all 9 patients. There were no dose-limiting toxicities. All patients showed progressive disease (PD), except 1 patient showed stable disease for one month at end of study follow-up. Another patient had transient radiographic response of the intraventricular tumor after 5 infusions of NK cell before progressing to PD. At higher dose levels, NK cells increased in the CSF during treatment with repetitive infusions (mean 11.6-fold). Frequent infusions of NK cells resulted in CSF pleocytosis. Radiomic signatures were profiled in 7 patients, evaluating ability to predict upfront radiographic changes, although they did not attain statistical significance.Conclusions. This study demonstrated feasibility of production and safety of intraventricular infusions of autologous NK cells.These findings support further investigation of locoregional NK cell infusions in children with brain malignancies.