Conventional treatment, surgery, radiation therapy, and chemotherapy, has not improved the prognosis for patients with pediatric and adult malignant brain tumors. The median survival for children with disseminated medulloblastoma and for adult patients with glioblastoma multiforme is approximately 1 year. New, innovative treatment modalities need to be developed and tested in vivo before initiating clinical trials in patients with these diseases. Immunotoxins, toxic proteins linked to tumor-specific carrier molecules such as monoclonal antibodies or growth factors, may be appropriate for patients with central nervous system neoplasia because of the compartmentalized nature of the cerebrospinal fluid space where high concentrations of locally administered agents are possible. Preliminary studies with immunotoxins have shown in vitro efficacy in glioma, medulloblastoma, and melanoma tissue-culture cell lines. In vivo immunotoxin studies have demonstrated efficacy in a syngenetic guinea pig model of leukemic meningitis and in a melanoma meningitis model in the nude rat treated intrathecally. The first specific aim of this project is to demonstrate in vivo efficacy of the immunotoxin transferrin-pseudomonas exotoxin A (Tfn-PE) in a nude rat model of leptomeningeal neoplasia with the Daoy medulloblastoma-derived cell line. Therapeutic effect will be determined by a delay in the onset of paraplegia. Immunotoxin dose and delivery schedule with respect to time and =frequency will be optimized to achieve the greatest therapeutic response.
The second aim i s to develop and treat an animal model of intrathecal glioblastoma multiforme. After the model is established, therapeutic efficacy will be determined in animals treated with Tfn-PE. Similar therapeutic parameters will be evaluated in animals with intrathecal glioblastoma as were examined with medulloblastoma. Demonstration of therapeutic efficacy in animals with intrathecal medulloblastoma and glioblastoma multiforme treated with immunotoxins will support the development and clinical application of these agents to patients with leptomeningeal neoplasia.
| Wallenfriedman, M A; Conrad, J A; DelaBarre, L et al. (1999) Effects of continuous localized infusion of granulocyte-macrophage colony-stimulating factor and inoculations of irradiated glioma cells on tumor regression. J Neurosurg 90:1064-71 |
