Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma.
Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma.
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DOI：
10.1158/1078-0432.ccr-15-0428
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Jensen MC
中科院分区：
文献类型：
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作者：
Brown CE;Badie B;Barish ME;Weng L;Ostberg JR;Chang WC;Naranjo A;Starr R;Wagner J;Wright C;Zhai Y;Bading JR;Ressler JA;Portnow J;D'Apuzzo M;Forman SJ;Jensen MC
首次人体试点安全性和可行性试验，评估嵌合抗原受体 (CAR) 工程化、自体原代人 CD8+ 溶细胞 T 淋巴细胞 (CTL) 靶向 IL13Rα2 用于治疗复发性胶质母细胞瘤 (GBM)。三名复发性 GBM 患者接受靶向 IL13Rα2 的 IL13(E13Y)-zetakine CD8+ CTL 治疗。患者通过导管/储库系统接受最多 12 次局部输注，最大剂量为 108 个 CAR 工程 T 细胞。我们证明了制造足够数量的表达 IL13(E13Y)-zetakine CAR 的自体 CTL 克隆的可行性，用于为一组诊断为 GBM 的患者重定向 HLA 独立的 IL13Rα2 特异性效应功能。将 IL13-zetakine+ CTL 克隆颅内递送至三名复发性疾病患者的切除腔内，耐受性良好，暂时性中枢神经系统炎症可控。输注 IL13-zetakine+ CTL 后，在两名患者中观察到短暂抗神经胶质瘤反应的证据。对一名患者 T 细胞治疗前后肿瘤组织的分析表明，治疗后肿瘤内 IL13Rα2 的总体表达降低。另一名患者的 MRI 分析表明，IL13-zetakine+ T 细胞给药部位的肿瘤坏死体积增加。这些发现为颅内施用 IL13Rα2 特异性 CAR T 细胞治疗 GBM 提供了有希望的首次人体临床经验，为未来改进过继性 CAR T 细胞疗法奠定了基础。
A first-in-human pilot safety and feasibility trial evaluating chimeric antigen receptor (CAR) engineered, autologous primary human CD8+ cytolytic T lymphocytes (CTLs) targeting IL13Rα2 for the treatment of recurrent glioblastoma (GBM). Three patients with recurrent GBM were treated with IL13(E13Y)-zetakine CD8+ CTL targeting IL13Rα2. Patients received up to twelve local infusions at a maximum dose of 108 CAR-engineered T cells via a catheter/reservoir system. We demonstrate the feasibility of manufacturing sufficient numbers of autologous CTL clones expressing an IL13(E13Y)-zetakine CAR for redirected HLA-independent IL13Rα2-specific effector function for a cohort of patients diagnosed with GBM. Intracranial delivery of the IL13-zetakine+ CTL clones into the resection cavity of three patients with recurrent disease was well-tolerated, with manageable temporary CNS inflammation. Following infusion of IL13-zetakine+ CTLs, evidence for transient anti-glioma responses was observed in two of the patients. Analysis of tumor tissue from one patient before and after T cell therapy suggested reduced overall IL13Rα2 expression within the tumor following treatment. MRI analysis of another patient indicated an increase in tumor necrotic volume at the site of IL13-zetakine+ T cell administration. These findings provide promising first-in-human clinical experience for intracranial administration of IL13Rα2-specific CAR T cells for the treatment of GBM, establishing a foundation on which future refinements of adoptive CAR T cell therapies can be applied.