Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

tested on 31 patients who were resistant to chemotherapy. Among them, one had a complete remission and two had partial remissions following treatment with the drug that was administrated by intravenous (i.v.) infusion. Transferrin receptors (TfRs) are overexpressed on rapidly dividing cells and various tumor cells. While relatively scarce in healthy brain tissue, intense expression of TfRs can be found on tumor cells of glioblastoma multiforme (GBM's) [147] . Tf-CRM107, which is also called "transMID" is a conjugate protein of a mutant diphtheria toxin that lacks receptor-binding activity (CRM107) [148] , linked by a thioester bond to human transferrin (Tf) [149] . In Phase I clinical trials, TF-CRM107 was delivered by high-flow interstitial microinfusion into the tumor region and reduction in tumor volume occurred in nine of 15 patients who could be evaluated, including two complete responses. No symptomatic systemic toxicity occurred [32] . In the phase II clinical study, Tf-CRM107 treatment resulted in a 35% response rate: Of the 34 patients evaluable for efficacy, there were a total of five complete responders and seven partial responders. Infusions of Tf-CRM107 resulted in symptomatic progressive cerebral edema in eight of the total enrolled 44 patients (14%) that were responsive to medical management. Seizures were seen in three patients who responded to anticonvulsant therapy [33] . However, a conditional power analysis in phase III determined that Tf-CRM107 was unlikely to improve overall patient survival compared with the current standard of care, and it was decided to terminate the trial and further clinical development of the drug [34].