脑内给予 CTLA-4 和 PD-1 免疫检查点阻断单克隆抗体治疗复发性胶质母细胞瘤患者的 I 期临床试验

BACKGROUND: Patients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30-39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated. METHODS: Within 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue. RESULTS: Twenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1-4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2-152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029). CONCLUSION: IC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS. TRIAL REGISTRATION: NCT03233152.

背景：在前瞻性临床试验中，复发性胶质母细胞瘤（rGB）患者的总体预后较差，中位总生存期（OS）为 30-39 周。静脉注射程序性细胞死亡蛋白 1 和细胞毒性 T 淋巴细胞相关抗原 4 抑制剂在 rGB 患者中的活性较低。在这项 I 期临床试验中，研究了颅内（IC）给予伊匹单抗（IPI）和纳武利尤单抗（NIVO）联合静脉给予 NIVO。

方法：在静脉给予固定剂量（10mg）NIVO 后 24 小时内，患者接受最大安全切除，然后在切除腔衬里的脑组织中注射 IPI（10mg；队列 1）或 IPI（5mg）加 NIVO（10mg；队列 2）。每 2 周重复静脉给予 NIVO（10mg）（最多 5 次）。对切除的肿瘤组织进行下一代测序和 RNA 基因表达谱分析。

结果：共纳入 27 例患者（队列 1：n=3；队列 2：n=24）。所有患者均接受了最大安全切除和计划的 IC 给药以及术前 NIVO。13 例患者（队列 1：n=3；队列 2：n=10）接受了所有 5 次术后静脉 NIVO 剂量。在队列 2 中，14 例患者接受了中位数为 3 次（范围 1-4 次）的静脉给药。2 例患者在接受类固醇治疗后出现亚急性术后神经恶化（n=2），可逆转；未观察到其他中枢神经系统毒性。免疫相关不良事件罕见且轻微。26 例患者诊断为 GB 复发（中位无进展生存期（PFS）为 11.7 周（范围 2-152））；21 例患者因进展而死亡。中位 OS 为 38 周（95%CI：27 至 49），6 个月、1 年和 2 年 OS 率分别为 74.1%（95%CI：57 至 90）、40.7%（95%CI：22 至 59）和 27%（95%CI：9 至 44）。OS 优于历史队列（描述性对数秩检验 p>0.003）。PFS 无显著差异（描述性对数秩检验 p>0.05）。B7-H3 肿瘤 mRNA 表达水平较高与生存显著相关（多变量 Cox 逻辑回归，p>0.029）。

结论：rGB 最大安全切除后，IC 给予 NIVO 和 IPI 是可行的、安全的，并与令人鼓舞的 OS 相关。

试验注册：NCT03233152。