IMMUNOTHERAPY FOR MALIGNANT GLIOMAS

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The limitation of current therapy for patients with malignant gliomas, together with the availability of cytokines with well defined immunomodulatory properties, have led to renewed interest in immunotherapy. The purpose of the proposed research is to identify potentially effective forms of immunotherapy for further study in clinical trials. This will be achieved by examining human glioma tissue for factors which may be contributing to the ability of malignant gliomas to evade the host immune response and using a syngeneic rat glioma model to evaluate various strategies of immunotherapy. The proposed research will consist of two parts: 1) The immune parameters within surgical specimens of human glioma tissue (discarded tissue), including the composition of the inflammatory infiltrate, and the expression of major histocompatibility complex (MHC) antigens and the accessory molecules (LFA 3) will be examined immunocytochemically. This will provide a standard for comparison with the immune parameters in the syngeneic rat glioma model. These immune parameters will also be correlated with clinical and histologic features. The hypothesis that the relative absence of MHC antigens and accessory molecules and the presence of suppressor inducer CD4+,2H4+ lymphocytes may be contributing to the ability of malignant gliomas to evade the host immune response will be examined. 2) A syngeneic rat glioma model which reflects the immunologic characteristics of malignant gliomas will be used to evaluate various strategies of immunotherapy. The principle strategy will involve the use of cytokines to increase MHC expression on tumor cells, rendering them more susceptible to T cell mediated immune responses. Additional strategies that will be examined include a) overcoming the effects of immunosuppressive factors released by glioma cells with interleukin-2 and tumor necrosis factor, b) augmenting lymphokine activated killer (LAK) cell and interleukin-2 (IL-2) activity by inducing HLA-DR expression on the tumor cells and c) using chemotherapy directed towards the elimination of suppressor T cells.