The central nervous system (CNS) has long been regarded as an immunologically privileged site. Immunotherapies effective in controlling cancers in other sites have failed to prevent tumor progression in the CNS. Dendritic cells (DCs) are the most efficient antigen-presenting cells (APCs). Following co-culture with tumor antigens, DCS can induce expansion of tumor-specific T-cells. As brain tumors may not be exposed to fully activated APCs in the CNS, exploring DC-based therapies for CNS tumors will provide a valuable opportunity to gain fundamental information about the unique features of the CNS tumor environment that will be of critical significance for developing this innovative therapeutic approach. In this project, we present preliminary data supporting the induction of anti-glioma immunity using DC-based vaccines; and present a plan for the development of effective DC-based therapies for malignant brain tumors.
Our Specific Aims i nclude: 1) Optimize the induction of tumor-specific effector cells using DCS in a series of rodent glioma models; 2) Develop strategies that effectively combine DC-based peripheral vaccination and alteration of the tumor microenvironment; 3) Initiate clinical trials to test the feasibility and safety of these approaches. The efficacy of DC-based vaccination appears to be promising, however, still limited for the treatment of established CNS gliomas. To improve the efficacy of DC- based vaccine strategies we will utilize rat glioma cell lines and DCs for preclinical assessment. We will first optimize the loading conditions of DCS with tumor cell antigens by examining different preparations of glioma antigens, and identifying which cytokines or combination of cytokines achieve maximal potentiation of DC activation at the vaccine site. Also, transfection of DCS with a gene vector that expresses the cytokine determined as critical in these analyses will be examined to enhance the anti-tumor response. In addition, we will determine if modification of the target intracranial tumor microenvironment using radiosurgery or cytokine gene delivery can enhance the efficacy of DC- based immunotherapy by up-regulating the trafficking and activity of anti-tumor effector cells. Clinical protocols will be developed on the basis of these preclinical studies. Taken together, the proposed studies may provide a strong basis for the development of DC-based vaccine strategies as independent therapeutic approaches for malignant gliomas; and also demonstrate extensive applications of DC-based vaccines in combination with other biologic therapy appr4oaches (i.e., gene therapy, apoptosis induction, and stereotactic radiosurgery) to enhance the efficacy of each single modality.
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