Bagley Stephen J, Desai Arati S, Fraietta Joseph A, Silverbush Dana, Chafamo Daniel, Freeburg Nelson F, Gopikrishna Gayathri Konanur, Rech Andrew J, Nabavizadeh Ali, Bagley Linda J, Park Jungmin, Jarocha Danuta, Martins Rene, Sarmiento Nicolas, Maloney Eileen, Lledo Lester, Stein Carly, Marshall Amy, Leskowitz Rachel M, Jadlowsky Julie K, Mackey Shane, Christensen Shannon, Oner Bike Su, Plesa Gabriela, Brennan Andrea, Gonzalez Vanessa, Chen Fang, Barrett David, Colbourn Robert, Nasrallah MacLean P, Mourelatos Zissimos, Hwang Wei-Ting, Alanio Cecile, Siegel Donald L, June Carl H, Hexner Elizabeth O, Binder Zev A, O'Rourke Donald M
Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Glioblastoma Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Med. 2025 Jun 1. doi: 10.1038/s41591-025-03745-0.
Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a median overall survival (OS) of 12-15 months. Effective therapy for recurrent GBM (rGBM) following frontline chemoradiation is a major unmet medical need. Here we report the dose escalation and exploration phases of a phase 1 trial investigating intracerebroventricular delivery of bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) epitope 806 and interleukin-13 receptor alpha 2 (IL-13Rα2), or CART-EGFR-IL13Rα2 cells, in patients with EGFR-amplified rGBM. Primary endpoints included dose-limiting toxicity, determination of the maximum tolerated dose and recommended dose for expansion, and occurrence of adverse events. Secondary endpoints included objective radiographic response, duration of response, progression-free survival and OS. A total of 18 patients received CART-EGFR-IL13Rα2 cells. The maximum tolerated dose was determined to be 2.5 × 10 cells. Of the 18 patients, 10 (56%) experienced grade 3 neurotoxicity; none had grade 4-5 neurotoxicity. Of 13 patients, 8 (62%) with measurable disease at the time of CAR T cell infusion experienced tumor regression, with one confirmed partial response by Modified Response Assessment in Neuro-Oncology criteria (objective radiographic response, 8%; 90% confidence interval, 0-32%) and one patient with ongoing durable stable disease lasting over 16 months. Median progression-free survival was 1.9 months (90% confidence interval, 1.1-3.4 months), and median OS was not yet reached at the time of data cut-off (median follow-up time, 8.1 months). These findings indicate that intracerebroventricular delivery of bivalent CART-EGFR-IL13Rα2 is feasible and appears safe. CART-EGFR-IL13Rα2 cells are bioactive and exhibit a signal of antitumor effect in rGBM. ClinicalTrials.gov registration: NCT05168423 .
胶质母细胞瘤（GBM）是成人中最常见的原发性脑癌，中位总生存期（OS）为12至15个月。一线放化疗后复发性GBM（rGBM）的有效治疗是一项尚未满足的重大医疗需求。在此，我们报告了一项1期试验的剂量递增和探索阶段，该试验研究了向表皮生长因子受体（EGFR）表位806和白细胞介素-13受体α2（IL-13Rα2）靶向的二价嵌合抗原受体（CAR）T细胞，即CART-EGFR-IL13Rα2细胞，经脑室内递送至EGFR扩增的rGBM患者体内的情况。主要终点包括剂量限制性毒性、确定最大耐受剂量和推荐的扩展剂量以及不良事件的发生情况。次要终点包括客观影像学反应、反应持续时间、无进展生存期和总生存期。共有18例患者接受了CART-EGFR-IL13Rα2细胞治疗。确定最大耐受剂量为2.5×10个细胞。在这18例患者中，10例（56%）出现3级神经毒性；无4至5级神经毒性。在13例患者中，8例（62%）在输注CAR T细胞时疾病可测量，出现肿瘤消退，其中1例根据神经肿瘤学改良反应评估标准确认为部分缓解（客观影像学反应，8%；90%置信区间，0至32%），1例患者持续疾病稳定超过16个月。中位无进展生存期为1.9个月（90%置信区间，1.1至3.4个月），在数据截止时中位总生存期尚未达到（中位随访时间，8.1个月）。这些发现表明，脑室内递送二价CART-EGFR-IL13Rα2是可行的且似乎是安全的。CART-EGFR-IL13Rα2细胞具有生物活性，并在rGBM中表现出抗肿瘤作用信号。ClinicalTrials.gov注册号：NCT05168423 。
