Adoptive cellular immunotherapy has been used with reasonable efficacy (10- 20%) against metastatic systemic cancers, primarily malignant melanoma and renal cell carcinoma. We have tested the efficacy of this therapy in adults with primary malignant glioma with encouraging results. The host and tumor factors that determine the beneficial effect of this modality, however, are poorly understood. the overall goal of this project is to augment the tumor cell killing by activating endogenous natural killer (NK) cell activity and the adoptive transfer of highly lytic effector cells. The use of multiple, activating cytokines of specific monoclonal antibodies may further potentiate the cellular immune response against primary brain tumors. We will attempt to identify and characterize cell surface molecules that facilitate natural killer cell and/or lymphokine activated killer (LAK) cell-mediated immune recognition and killing of primary brain tumors in vitro by using isolated NK/LAK resistant tumor clones, and glioma spheroids. Brain tumor clones will be derived from adult and pediatric brain tumors to study mechanisms of NK and LAK cell resistance. Antibodies directed against growth factor receptors (e.g. EGF-R), oncogene proteins (e.g. erbB2) or integrin adhesion molecules (e.g. VCAM, VLA-4) will be tested to determine if they positively or negatively affect tumor cell cytolysis. In addition, we will attempt to augment the immune response to primary brain tumors using cytokines (eg. IFN-beta, TNF-alpha, IL-1, IL-6) to increase tumor susceptibility to lysis, and antibody dependent cellular cytotoxicity (ADCC).
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