We are investigating a new approach for the treatment of brain tumors which utilizes a 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) 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 methods are being developed to demonstrate drug distribution in patients. We have completed a phase I trial of regional therapy with the targeted protein toxin transferrin-CRM 107 (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 Tf receptor, which facilitates iron uptake and is present in higher number on tumor cells than on the normal cells of the brain; the diphtheria toxin mutant kills tumor cells to which the Tf-CRM107 binds. The purpose of the Phase I study was 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-seven patients with malignant brain tumors refractory to standard therapy (surgery, radiation chemotherapy) were treated. The results indicated that therapy with Tf-CRM107 produces tumor responses without severe neurologic or systemic toxicity. A multicenter Phase II study has now begun. Synergism between targeted protein toxins and other antitumor agents, including standard chemotherapy drugs and retinoids, is under investigation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002855-07
Application #
6111896
Study Section
Special Emphasis Panel (SNB)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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