The primary hypothesis of this proposal is that improved delivery of operationally specific radiolabeled monoclonal antibodies (MAbs) or their fragments, and selected chemotherapeutic drugs to intracranial tumors can be achieved by 1) varying the route of delivery (intravenous, intracarotid, intrathecal, or intratumoral), 2) the use of more freely diffusible, high-affinity Fab or F(ab')2 fragments, and 3) temporary disruption of the blood-brain barrier (BBB), which restricts the entry of low-molecular weight, water- soluble compounds, as well as higher molecular weight proteins, such as MAbs. Current therapeutic agents are limited by inadequate delivery to tumor, lack of specificity for tumor, and genotypic and phenotypic heterogeneity in tumor. Monospecific MAbs offer the potential for specific therapy of tumor with minimal toxicity to the normal CNS. Genotypic and phenotypic heterogeneity may be overcome by using a panel of MAbs of differing tumor specificities. Studies from our laboratory during the previous grant period have demonstrated that even a single 131I-MAb (81C6) may show therapeutic efficacy after systemic administration in subcutaneous and intracranial human glioma xenografts. Most human gliomas are significantly less permeable than glioma xenografts, however, and preliminary clinical trials with MAbs in patients have shown specific localization sufficient for imaging studies, but not sufficient for therapeutic trials.
Our specific aims are to determine if the demonstrated localization advantage of MAb fragments may be exploited to yield a greater therapeutic advantage, as well as determine the potential role of BBB disruption in the therapy of malignant gliomas. Methods to be investigated include hyperosmolar disruption with mannitol, adenosine, etoposide, interleukin-2, leukotriene, and interstitial radiation induced BBB disruption. Using a recently developed model of neoplastic meningitis, the role of intrathecal administration of MAbs will be investigated. Finally, the efficacy of various routes of delivery of chemotherapeutic agents to human glioma xenografts in athymic rats (including intravenous, intracarotid, and intracarotid with BBB disruption will be investigated.
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