title: Clinical studies with targeted toxins in malignant glioma.
abstract: 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.
authors.affiliation: 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. rainov@liv.ac.uk
authors.forename: Nikolai G
authors.initials: NG
authors.lastname: Rainov
authors.forename: Ariane
authors.initials: A
authors.lastname: Söling
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000628:therapy*; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems / Q000379:methods; D005098:Exotoxins / Q000627:therapeutic use*; D005910:Glioma / Q000628:therapy*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D000922:Immunotoxins / Q000627:therapeutic use*; D018793:Interleukin-13 / Q000627:therapeutic use; D015847:Interleukin-4 / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014168:Transferrin / Q000627:therapeutic use; D016211:Transforming Growth Factor alpha / Q000627:therapeutic use*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D001427:Bacterial Toxins; D005098:Exotoxins; D007155:Immunologic Factors; D000922:Immunotoxins; D018793:Interleukin-13; D015847:Interleukin-4; D011993:Recombinant Fusion Proteins; D014168:Transferrin; D016211:Transforming Growth Factor alpha; C521502:IL13-PE38; C404391:Tf-CRM107; C479467:interleukin-4-Pseudomonas exotoxin; C529632:transforming growth factor(alpha)-Pseudomonas aeruginosa exotoxin (38); D000097668:Pseudomonas aeruginosa Exotoxin A