Shimamura Takeshi, Husain Syed R, Puri Raj K
Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, Maryland 20892, USA.
Neurosurg Focus. 2006 Apr 15;20(4):E11. doi: 10.3171/foc.2006.20.4.6.
Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for brain tumor therapy. The authors have discovered that receptors for two cytokines, interleukin (IL)-4 and IL-13, are overexpressed on tumor biopsy samples and on cell lines derived from a variety of human tumors, including brain tumors. These investigators have demonstrated that the structure of these cytokine receptors on tumor cells is different from that found on normal immune cells. In human solid tumor cells, IL-4 binds to two chains (IL-4Ra and IL-13Ra1), whereas IL- 13 binds to three chains in many solid tumor cells, including glioma cells (to IL-4Ra, IL-13Ra1, and IL-13Ra2). To target IL-4Rs and IL-13Rs, the authors generated two recombinant fusion cytotoxins composed of IL-4 or IL-13 and a mutated form of pseudomonas exotoxin (PE), which for simplicity are called IL4-PE and IL13-PE in this paper. These chimeric cytotoxins are highly toxic in vitro to human tumor cell lines and primary cell cultures, including glioma cells, and in vivo to animal models of human tumors, including gliomas. In contrast, normal cells, including immune, endothelial, and brain cells, are spared from their cytotoxic effects. Based on numerous preclinical studies, IL13-PE (also known as IL13-PE38QQR or cintredekin besudotox) has been tested in four Phase I/II clinical trials. The agent IL13-PE was administered intracranially by using convection-enhanced delivery (CED). The drug was delivered through catheters placed either directly into the tumor bed or in the peritumoral region after resection of the lesion. The CED of IL13-PE was fairly well tolerated, with a reasonable benefit/risk profile for treatment of patients with glioma. Based on Phase I/II clinical trials, the Phase III Randomized Evaluation of CED of IL13-PE Compared to Gliadel Wafer with Survival Endpoint Trial (also known as the PRECISE Trial) in patients with initial recurrence of glioblastoma multiforme has recently been completed. Patients are being monitored for safety of the agents, duration of overall survival, and quality of life.
用细胞毒素或免疫毒素靶向细胞表面受体为脑肿瘤治疗提供了独特的机会。作者发现，两种细胞因子白细胞介素（IL）-4和IL-13的受体在肿瘤活检样本以及源自包括脑肿瘤在内的多种人类肿瘤的细胞系上过度表达。这些研究人员已证明，肿瘤细胞上这些细胞因子受体的结构与正常免疫细胞上的不同。在人类实体瘤细胞中，IL-4与两条链（IL-4Ra和IL-13Ra1）结合，而在包括胶质瘤细胞在内的许多实体瘤细胞中，IL-13与三条链结合（与IL-4Ra、IL-13Ra1和IL-13Ra2结合）。为了靶向IL-4Rs和IL-13Rs，作者制备了两种重组融合细胞毒素，它们由IL-4或IL-13与一种突变形式的绿脓杆菌外毒素（PE）组成，在本文中为简便起见将其称为IL4-PE和IL13-PE。这些嵌合细胞毒素在体外对包括胶质瘤细胞在内的人类肿瘤细胞系和原代细胞培养物具有高度毒性，在体内对包括胶质瘤在内的人类肿瘤动物模型也具有高度毒性。相比之下，包括免疫细胞、内皮细胞和脑细胞在内的正常细胞则免受其细胞毒性作用。基于大量临床前研究，IL13-PE（也称为IL13-PE38QQR或cintredekin besudotox）已在四项I/II期临床试验中进行了测试。通过对流增强递送（CED）将IL13-PE药物颅内给药。药物通过直接置于肿瘤床或在病变切除后置于瘤周区域的导管递送。IL13-PE的CED耐受性相当良好，对胶质瘤患者治疗的获益/风险比合理。基于I/II期临床试验，最近已完成了多形性胶质母细胞瘤初次复发患者的IL13-PE与Gliadel薄片相比的CED生存终点III期随机评估试验（也称为PRECISE试验）。正在对患者进行药物安全性、总生存期和生活质量的监测。
