Duke University Medical Center, Department of Neurosurgery, Durham, North Carolina, USA.
Loma Linda University Medical Center, Department of Neurosurgery, Loma Linda, California, USA.
Neuro Oncol. 2023 Jun 2;25(6):1085-1097. doi: 10.1093/neuonc/noac285.
MDNA55 is an interleukin 4 receptor (IL4R)-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the tumor microenvironment. High expression of IL4R is associated with poor clinical outcomes.
MDNA55-05 is an open-label, single-arm phase IIb study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and nonresectable at recurrence) on their 1st or 2nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection-enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10μL/min to ensure that the infusion duration did not exceed 48 h. The primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS.
MDNA55 showed an acceptable safety profile at doses up to 240 μg. In all evaluable patients (n = 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (n = 32) consisting of IL4R High and IL4R Low patients treated with high-dose MDNA55 (>180 ug) showed the best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26).
MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high-dose irrespective of IL4R expression level.Trial Registration: Clinicaltrials.gov NCT02858895.
MDNA55 是一种白细胞介素 4 受体（IL4R）靶向毒素，目前正在开发用于复发性 GBM，这是一种普遍致命的疾病。IL4R 在 GBM 以及肿瘤微环境中的细胞中过度表达。高表达 IL4R 与不良临床结局相关。
MDNA55-05 是一项开放标签、单臂 IIb 期研究，评估 MDNA55 在复发性 GBM（rGBM）患者中的疗效，这些患者在首次或第二次复发时具有侵袭性 GBM（新诊断的 GBM、IDH 野生型和不可切除的复发）。MDNA55 通过使用对流增强递送（CED）以单次剂量（剂量范围为 18 至 240μg）进行瘤内给药，最多使用 4 个立体定向放置的导管。它与造影剂（钆-DTPA，Magnevist®）共同输注，以评估肿瘤边缘内外的分布情况。每个导管的流速不超过 10μL/min，以确保输注时间不超过 48 h。主要终点是 mOS，次要终点确定 IL4R 状态对 mOS 和 PFS 的影响。
在高达 240μg 的剂量下，MDNA55 显示出可接受的安全性特征。在所有可评估的患者（n=44）中，mOS 为 11.64 个月（80%单侧置信区间 8.62，15.02），OS-12 为 46%。一个亚组（n=32）由高剂量 MDNA55（>180μg）治疗的 IL4R High 和 IL4R Low 患者组成，mOS 为 15 个月，OS-12 为 55%，显示出最佳获益。根据 mRANO 标准，观察到 81%（26/32）的肿瘤控制，包括表现出假性进展的患者（15/26）。
MDNA55 显示出肿瘤控制和有希望的生存获益，并且当以高剂量治疗时，可能对 rGBM 患者有益，无论 IL4R 表达水平如何。
Clinicaltrials.gov NCT02858895。
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