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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02893-z

摘要内容如下：

复发性胶质母细胞瘤（RGBM）仍然是主要的未满足的医疗需求，中位总生存期不到1年在此，我们报道了在鞘内递送靶向表皮生长因子受体（EGFR）和白细胞介素-13受体α2（IL13Rα2）的二价嵌合抗原受体（CAR）T细胞的1期试验中治疗的首批6例RGBM患者。该研究的主要终点是安全性和最大耐受剂量的确定。该中期分析中报告的次要终点包括制造失败的频率和根据神经肿瘤学标准中的改良反应评估的客观放射学反应（ORR）。所有6名患者在治疗时均有进行性多灶性疾病。在两个剂量水平1（1×107个细胞；n=3）和剂量水平2（2.5×107个细胞；n=3），给予CART-EGFR-IL13Rα2细胞与早发性神经毒性相关，最符合免疫效应细胞相关神经毒性综合征（ICANS），并用高剂量地塞米松和阿那白滞素（抗IL1R）治疗。剂量水平为2的一名患者出现剂量限制性毒性（3级厌食、全身性肌无力和疲劳）。在所有6名患者中，在早期磁共振成像时间点观察到增强和肿瘤大小的减少；然而，没有人符合ORR的标准。在探索性终点分析中，在所有6名患者的脑脊液中检测到大量的CAR T细胞丰度和细胞因子释放。总之，这些首次在人类中的数据证明了RGBM中CART-EGFR-IL13Rα2细胞的初步安全性和生物活性。还检测到令人鼓舞的早期疗效信号，需要更多的患者和更长的随访时间进行确认。ClinicalTrials.gov标识符：NCT05168423。

英文原文如下：

Abstracts

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .

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