Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial

IF 58.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Stephen J. Bagley, Arati S. Desai, Joseph A. Fraietta, Dana Silverbush, Daniel Chafamo, Nelson F. Freeburg, Gayathri Konanur Gopikrishna, Andrew J. Rech, Ali Nabavizadeh, Linda J. Bagley, Jungmin Park, Danuta Jarocha, Rene Martins, Nicolas Sarmiento, Eileen Maloney, Lester Lledo, Carly Stein, Amy Marshall, Rachel M. Leskowitz, Julie K. Jadlowsky, Shane Mackey, Shannon Christensen, Bike Su Oner, Gabriela Plesa, Andrea Brennan, Vanessa Gonzalez, Fang Chen, David Barrett, Robert Colbourn, MacLean P. Nasrallah, Zissimos Mourelatos, Wei-Ting Hwang, Cecile Alanio, Donald L. Siegel, Carl H. June, Elizabeth O. Hexner, Zev A. Binder, Donald M. O’Rourke
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引用次数: 0

Abstract

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 × 107 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.

Abstract Image

靶向EGFR和IL-13Rα2的脑室内二价CAR - T细胞治疗复发性胶质母细胞瘤:一项1期试验
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12-15个月。一线放化疗后复发性GBM (rGBM)的有效治疗是一个主要的未满足的医疗需求。在这里,我们报告了一项研究双价嵌合抗原受体(CAR) T细胞靶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)或CART-EGFR-IL13Rα2细胞在EGFR扩增的rGBM患者脑室内递送的剂量递增和探索阶段。主要终点包括剂量限制性毒性,最大耐受剂量和扩展推荐剂量的确定,以及不良事件的发生。次要终点包括客观放射学反应、反应持续时间、无进展生存期和OS。共有18例患者接受了CART-EGFR-IL13Rα2细胞治疗。测定最大耐受剂量为2.5 × 107个细胞。在18例患者中,10例(56%)出现3级神经毒性;无4-5级神经毒性。在13例患者中,8例(62%)在CAR - T细胞输注时可测量的疾病出现肿瘤消退,其中1例经神经肿瘤学标准的改良反应评估证实部分缓解(客观放射学反应,8%;90%置信区间,0-32%),1例患者持续持续,病情稳定,持续时间超过16个月。中位无进展生存期为1.9个月(90%置信区间为1.1-3.4个月),截止数据时尚未达到中位OS(中位随访时间为8.1个月)。这些结果表明,二价CART-EGFR-IL13Rα2脑室内递送是可行的,并且是安全的。CART-EGFR-IL13Rα2细胞具有生物活性,在rGBM中表现出抗肿瘤作用信号。ClinicalTrials.gov注册:NCT05168423。
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来源期刊
Nature Medicine
Nature Medicine 医学-生化与分子生物学
CiteScore
100.90
自引率
0.70%
发文量
525
审稿时长
1 months
期刊介绍: Nature Medicine is a monthly journal publishing original peer-reviewed research in all areas of medicine. The publication focuses on originality, timeliness, interdisciplinary interest, and the impact on improving human health. In addition to research articles, Nature Medicine also publishes commissioned content such as News, Reviews, and Perspectives. This content aims to provide context for the latest advances in translational and clinical research, reaching a wide audience of M.D. and Ph.D. readers. All editorial decisions for the journal are made by a team of full-time professional editors. Nature Medicine consider all types of clinical research, including: -Case-reports and small case series -Clinical trials, whether phase 1, 2, 3 or 4 -Observational studies -Meta-analyses -Biomarker studies -Public and global health studies Nature Medicine is also committed to facilitating communication between translational and clinical researchers. As such, we consider “hybrid” studies with preclinical and translational findings reported alongside data from clinical studies.
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