Interstitial therapy with targeted protein toxins for malignant brain tumors: 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. Initially we 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 been finished. The results suggest similar efficacy and toxicity as was observed in the Phase I trial. A new protocol to investigate the safety of perfusing the region of brain surrounding tumor excision to eliminate infiltrating tumor cells and to examine the potential of protecting the brain, but not tumor, with this approach combined with systemic administration of chloroquine, an agent that inhibits endothelial cell injury by Tf-CRM 107, is being prepared. Vascular permeability factor/vascular endothelial growth factor in the CNS: Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a protein secreted by many cell types which has been shown in model systems unrelated to the central nervous system (CNS) to perform two major functions: it is an angiogenic, endothelial-specific growth factor, and a potent inducer of vascular leakage. Our continuing goals are to define the function of VEGF in the central nervous system, to understand the extent to which altered expression of VEGF contributes to the development of certain pathologic conditions, and to develop strategies for modifying the activity of VEGF in appropriate clinical settings. Recently our work has emphasized investigation of the direct effects of VEGF on normal brain. Since increased VEGF expression has been associated with several CNS pathologies (including brain tumors) these findings have ramifications for the understanding/treatment of the brain edema and inappropriate angiogenesis associated with various CNS diseases. The results indicate:1) Chronic overexposure of normal brain to VEGF greatly increases the capillary permeability to both large and small molecules, resulting in focal blood-brain barrier (BBB) disruption without cell destruction, inflammation, or neurologic deficit. VEGF administration may permit a prolonged, nontoxic method for opening the BBB in order to enhance delivery of a variety of substances into the brain for experimental or therapeutic purposes. Alternatively, specific inhibition of VEGF expression/action might restore normal cerebral vascular function in situations where BBB disruption exists. 2) VEGF alone does not elicit an inflammatory response. However, VEGF can liberate an immune response to a foreign antigen (e.g. a virus) already present in the CNS. VEGF potentiates inflammation in CNS not only by opening the BBB and allowing contact between normally sequestered antigens and blood-borne immune mediators, but also by inducing immune mediators such as intercellular adhesion molecules and major histocompatibility complex class I and II expression in the CNS. The modulation of inflammation in the CNS by VEGF may have ramifications for inflammatory diseases of the CNS such as multiple sclerosis. 3) Although VEGF administration is sufficient to induce angiogenesis outside of the nervous system, the normal brain is relatively refractory to VEGF-induced angiogenesis. Other perturbations (e.g. a brain tumor) must be present in conjunction with VEGF in order to induce CNS angiogenesis. This may be explained by differential expression of VEGF receptors in normal brain vessels compared to tumor-associated vessels. The altered profile of VEGF receptors on brain tumor blood vessels allows a selective targeting of tumor vessels through VEGF receptor-specific toxins. However, such toxins are unable to target small infiltrative tumors not yet dependent on VEGF-mediated angiogenesis. Approaches to target tumor blood vessels at earlier stages of development are being sought. Glioblastoma multiforme after whole brain irradiation: To determine the acute and long-term effects of a therapeutic dose of whole brain radiation in a primate model, we studied the outcome in monkeys that received whole brain irradiation. Twelve male primates (Macaca mulatta) underwent fractionated (350 cGy 5 days a week for 2 weeks) whole brain irradiation (total dose 3500 cGy). Animals were followed clinically, with laboratory studies, and serial magnetic resonance (MR)-imaging. They were sacrificed when they developed medical problems, neurological symptoms, lesions on MR-imaging, or at the study completion. Nine (75%; 5 control and 4 pentobarbital animals) of 12 animals developed neurologic symptoms, and/or enhancing lesions on MR-imaging that were histopathologically diagnosed as glioblastoma multiforme (GBM) (2.9 to 8.3 years after irradiation). GBMs were either unifocal (n=2) or multifocal (n=7), and were located in the supratentorial (n=6), infratentorial (n=2), or both (n=1) cranial region(s). All GBMs demonstrated hypercellularity, giant cell, cellular pleomorphism, neovascularity, and extensive infiltration along white matter tracts and Virchow-Robin spaces. The three animals that did not develop GBMs were euthanized after either developing medical problems (2.5 years; n=1) or study completion (10 years; n=2), and had no radiographic or histologic evidence of central nervous system (CNS) disease. Thus, we discovered that there is a high rate of (75%) of GBM formation with therapeutic doses of whole brain radiation, suggesting that radioinduction of these neoplasms in primate CNS tissue may not be an infrequent late complication of this therapy. Moreover, this infiltrative glioma model, which has histopathological characteristics identical to gliomas in humans, is being used for investigation of the anatomy and mechanism of tumor infiltration, to characterize infiltrating glioma cells, and potential therapeutic modalities.
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