Spread of cancer into the cerebrospinal fluid (CSF) is painful, debilitating and lethal. It occurs in 20% of childhood and adult brain tumors and an increasing percentage of systemic tumors. There is presently no lasting effective therapy for overt disease and the average life expectancy is 6 months with meningeal spread from a systemic cancer and 12 months with spread from a primary brain tumor. The major objective of this project is to develop new therapies for leptomeningeal (LM) neoplasia that utilize monoclonal antibodies (MoAbs). Specific treatment will include unmodified MoAbs alone or in combination with cytokines or growth factors such as IL-1, IL-2, TNF, and G-CSF. The mechanisms of anti-tumor effect will be studied by standard histologic and immunohistologic analysis of the CSF, leptomeninges and brain; in vitro assays of CSF cytotoxicity, antibody dependent cytotoxicity and complement dependent cytotoxicity; variation of MoAb immunoglobulin class, fractions (e.g. F(Ab')2) and scheduling; and depletion of host cellular and complement inflammatory response. A xenograft model with human tumors will be utilized to explore various strategies and agents for treatment. The initial experiments will evaluate the pharmacokinetics, toxicity, anti-tumor effects, and mechanisms of action of intrathecal (IT) and intravenous (IV) 3F8 and R24 MoAbs in athymic rats with LM xenografts of human melanoma, medulloblastoma or neuroblastoma. These MoAbs are in clinical trials for the treatment of human neuroblastoma and melanoma and have produced some promising results for the treatment of systemic disease. Our major hypothesis is that IT MoAb will be therapeutic against LM tumors which express the target antigen. Specific predictions are that IT-administered MoAb will distribute rapidly throughout the accessible CSF space and penetrate several mm into nervous tissue parenchyma; the specific binding of MoAb to tumor cells that express its target antigen will be 10 fold higher than non-specific binding to other tissues; IT MoAb will not be toxic to normal nervous system tissue; and sufficient complement and effector cells will enter the meningeal space to act with the MoAbs to eliminate tumor cells. The value of our anticipated results would be translation of the finding to clinical trials with these MoAbs for the treatment of LM disease in humans.
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