Despite aggressive surgical resections, high-dose radiation therapy, and chemotherapy delivered at toxic doses, the vast majority of patients with malignant brain tumors survive less than one year making conventional therapy for malignant brain tumors the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. Moreover, the failure of these treatment modalities to be tumor-specific at the molecular level, results in inevitable damage to surrounding normal brain that incapacitates patients treated with these traditional modalities. The inherent specificity of immunologic recognition offers the prospect of targeting malignant cells more precisely. Within our program, direct injection of 131-I-labeled, operationally-specific, monoclonal antibodies (MAbs) into brain tumor resection cavities delivers extremely high radiation doses to tumor cells around the resection cavity and has produced promising results in Phase II clinical trials. These MAbs diffuse only short distances beyond the cavity, however. Therefore, most of the radiation extending beyond the cavity is not specifically targeted to tumor cells and the radiation dose delivered beyond the cavity declines exponentially from the cavity interface. As a result tumor cells that are known to infiltrate the brain for significant distances beyond the cavity are sub-optimally treated and lethal tumors always recur within 2 cm of the radiated re section cavity. Continuous microinfusion is a promising technique that allows homogeneous delivery of even large molecular weight molecules at high concentrations throughout large areas of the brain. Although this technique may enhance the delivery of 131-I-labeled MAbs and other therapeutic agents to diffusely infiltrating malignant brain tumors and reduce recurrence rates, the parameters that govern this technique and its limitations have not been defined. One of the major goals of this proposal is to define these parameters. In addition, this proposal is designed to investigate whether targeted radiotherapy might be improved through the use of human chimeric MAbs with increased biostability and the use of high linear energy transfer radioisotopes, such as 211-At, with greater relative biological effectiveness.The hypothesis to be tested in this proposal is that continuous microinfusion will widely deliver operationally tumor-specific monoclonal antibodies conjugated to 131-I or the alpha-emitter 211-At such that they will be specific and potent therapeutic agents against malignant brain tumors with major reductions in toxicity to normal brain.
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