Rainov Nikolai G, Söling Ariane
The University of Liverpool, Dept. Neurological Science, The Walton Centre for Neurology and Neurosurgery NHS Trust, Clinical Sciences Centre for Research and Education, Lower Lane, Liverpool L9 7LJ, UK.
Rev Recent Clin Trials. 2006 May;1(2):119-31. doi: 10.2174/157488706776876454.
Targeted toxins represent a new class of agents with high specificity for tumor cells. Toxins in current clinical use for the treatment of brain tumors are mostly recombinant polypeptides consisting of a tumor-selective ligand coupled to a peptide toxin of bacterial origin. Targeted toxins are highly potent - one single molecule of toxin is enough to cause cell death. Toxins are able to kill tumor cells independent of any malignancy-associated genetic alterations and/or mutations. The blood-brain barrier has been a major obstacle for using targeted toxins for treatment of malignant glioma. Convection-enhanced delivery (CED), a method for delivery of large molecules to brain tissue via continuous interstitial microinfusion, has permitted direct administration of toxins to brain tumors or to surrounding brain tissue infiltrated by tumor cells. Four targeted toxins advanced to at least phase II clinical trials and are being used for treatment of adult or pediatric patients with recurrent or progressive malignant glioma. These are IL4-P. aeruginosa exotoxin (IL4-PE, NBI-3001), tumor growth factor (TGF)alpha-P. aeruginosa exotoxin (TP-38), IL13-P. aeruginosa exotoxin (IL13-PE38), and transferrin-C. diphtheriae toxin (TransMID(trade mark), Tf-CRM107). All of these toxins have shown an acceptable profile of toxicity and safety in phase I and II clinical studies and have demonstrated some evidence for tumor response. Current phase I and II clinical protocols are exploring several parameters, such as placement of catheters for CED either intratumorally or in the brain tissue surrounding a tumor, surgical resection of tumor before or after toxin infusion, and single vs. repeated infusion. Two large randomized and controlled phase III multicenter studies using IL13-PE38 or TransMID(trade mark) are currently enrolling patients. This review summarizes the study protocols and key findings of all previously completed and currently ongoing clinical studies with targeted toxins for malignant glioma. It offers in addition an outlook into future areas of development of targeted toxins, such as improved delivery modes and non-invasive in vivo imaging of intracerebral and intratumoral distribution of toxin in patients.
靶向毒素是一类对肿瘤细胞具有高特异性的新型药物。目前临床上用于治疗脑肿瘤的毒素大多是重组多肽，由与细菌来源的肽毒素偶联的肿瘤选择性配体组成。靶向毒素效力极强——单个毒素分子就足以导致细胞死亡。毒素能够杀死肿瘤细胞，而不受任何与恶性肿瘤相关的基因改变和/或突变的影响。血脑屏障一直是使用靶向毒素治疗恶性胶质瘤的主要障碍。对流增强递送（CED）是一种通过连续间质微输注将大分子递送至脑组织的方法，它允许将毒素直接施用于脑肿瘤或被肿瘤细胞浸润的周围脑组织。四种靶向毒素已进入至少II期临床试验，并正在用于治疗复发或进展性恶性胶质瘤的成人或儿童患者。它们分别是IL4-铜绿假单胞菌外毒素（IL4-PE，NBI-3001）、肿瘤生长因子（TGF）α-铜绿假单胞菌外毒素（TP-38）、IL13-铜绿假单胞菌外毒素（IL13-PE38）和转铁蛋白-白喉毒素（TransMID（商标），Tf-CRM107）。所有这些毒素在I期和II期临床研究中均显示出可接受的毒性和安全性概况，并已证明有一些肿瘤反应的证据。目前的I期和II期临床方案正在探索几个参数，如用于CED的导管是瘤内放置还是在肿瘤周围的脑组织中放置、毒素输注前后的肿瘤手术切除以及单次输注与重复输注。两项使用IL13-PE38或TransMID（商标）的大型随机对照III期多中心研究目前正在招募患者。本综述总结了所有先前完成的以及目前正在进行的使用靶向毒素治疗恶性胶质瘤的临床研究的方案和主要发现。此外，它还展望了靶向毒素未来的发展领域，如改进的递送方式以及对患者脑内和瘤内毒素分布的无创体内成像。
