IMMUNOBIOLOGICAL RESPONSES TO RAT BRAIN TUMOR VACCINES

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DESCRIPTION (Applicant's Description): Tumors of the central nervous system are anatomically and biologically distinct from cancers of other organ systems. They exist in an immunologically privileged state, and the mechanisms governing host immunologic responses to malignant glial neoplasms are incompletely understood. Malignant gliomas elude host defenses, in part, because the absence of conventional lymphatics in the central nervous system limits primary immune responses to brain tumors and because gliomas secrete factors, such as TGF-Beta2, which suppress systemic and local immune reactivity. The reduced T cell proliferative capacity in patients with gliomas and defects in the T cell IL-2 receptor may lead to clonal anergy and peripheral lymphocyte tolerance of brain tumor antigens. Further, modulated expression of critical adhesion molecules on tumor vascular endothelium may limit lymphocyte migration into central nervous system tumors. Nonetheless, the factors which promote host immunologic tolerance of gliomas are relative, not absolute, determinants of host immune reactivity. The investigators hypothesize that efficient brain tumor antigen processing and presentation can be accomplished through the use of genetically modified, cytokine expressing glioma vaccines and that such vaccines, as a consequence, will generate effective systemic immune responses and promote anti-tumor activity in the periphery as well as in the central nervous system. Interleukin-4 (IL-4) is a pleiotropic cytokine which activates vascular endothelia, promotes dendritic cell activation and proliferation, and serves as a T-cell growth factor. In preliminary studies using the 9L gliosarcoma cell line, and a 9L cell line the investigators have stably transfected with the murine interleukin-4 gene, they have shown that IL-4 promotes anti-tumor activity against 9L gliosarcomas in Fischer rats, that IL-4 anti-tumor effects are T-cell dependent, and that Fischer rats bearing 9L-IL4 tumors subsequently develop immunity to intracerebral or subcutaneous challenges with 9L gliosarcoma cells. To test their hypotheses, they propose: (1) to study the phenotype and function of tumor infiltrating lymphocytes in 9L gliosarcomas and their response to cytokines; (2) to analyze the mechanisms regulating lymphocyte infiltration into brain tumors; and (3) to evaluate the role of brain tumor vaccines in augmenting host immunologic responses to malignant gliomas. The long-term goal of this proposal is to understand better the mechanisms regulating specific immune responses to tumors of the central nervous system and to translate this knowledge into more effective biologic therapies of malignant glial neoplasms.