We are investigating a new approach for the treatment of brain tumors which utilizes new delivery approach for distribution of a class of potent, targeted anti-cancer compounds, called targeted protein toxins. Preclinical in vitro and in vivo experiments of toxins targeted to the transferrin receptor and epidermal growth factor (EGF) have demonstrated significant antitumor activity against a variety of tumor types including malignant gliomas. New methods of drug delivery have been developed to deliver these agents to brain tumors, and in vivo imaging method are being developed to demonstrate drug distribution in patients. We have initiated a dose escalation trial of regional therapy with the targeted protein toxin transferrin-CRM107 (Tf-CRM107) for the treatment of recurrent malignant brain tumors. Tf-CRM107 is a conjugate of human transferrin (Tf) and diphtheria toxin with a point mutation (CRM107). Tf- CRM107 binds to the transferrin receptor, which facilitates iron uptake and is present in higher number on tumor cells than on the normal cells of the brain, and the diphtheria toxin mutant kills these tumor cells to which the Tf-CRM107 binds. The purpose of the study is to evaluate the toxicity of Tf-CRM107 when delivered by intratumoral and peritumoral slow interstitial infusion in a dose escalation schedule and to assess antitumor activity in these patients. Twenty-one patients with malignant brain tumors refractory to standard therapy (surgery, radiation =/- chemotherapy) have been treated. Results indicate that therapy with Tf- CRM107 effects tumor responses, without severe neurologic or systemic toxicity. A multicenter Phase II study is being planned. In addition, an EGF-target toxin is being prepared for clinical trial. Synergism between targeted protein toxins and other antitumor reagents including standard chemotherapy drugs and retinoids is under investigation.
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