The long term goal of this research is to identify practical immunological adjuvants that can be utilized in the active specific immunotherapy of malignant tumors so as to make human tumor vaccines more therapeutically effective. We focus on two cytokines, IFN-gamma and GM-CSF; on the basis of findings in our own and other laboratories each is a T cell immunopotentiator. Emphasis is placed on altering not only the magnitude but the quality of the immune response since tumor inflammation per se is not necessarily associated with tumor regression. With syngeneic tumor cell vaccine we determine optimum parameters for cytokine immunoadjuvant administration, as measured by tumor growth inhibition and tumor regression in immunoprophylaxis and immunotherapeutic protocols. Coordinately, as a guide to construction of these protocols, we will analyze immunopotentiation of T cell reactivity to tumor cells as measured by delayed type hypersensitive (DTH), especially in tumor bearing mice. We will examine whether the addition of other immunoadjuvants such as cyclophosphamide, local BCG, Detox(R), local VP16 (etoposide) and probably other immunoadjuvants will further intensify the response. To investigate the mechanism of tumor inhibition, sample tumors at different time points from protocols causing tumor growth inhibition/regression and controls will be analyzed for infiltrating cells. cells will be analyzed by fluorescent activated cell sorter and by cytospin, and the cellular organization inspected by immunohistochemistry (frozen sections). Cytolytic T cells will be assessed for specific killing by a chromium release assay. Further, tumor infiltrating cells (and regional lymph nodes) will be characterized by analysis of cytokine secretion profile for the predominance of TH-1 or TH-2 CD-4 cells. (We test the hypothesis that TH-1 cells are associated with tumor rejection.) Measurement will be made of anti-tumor antibody and results integrated with other findings.
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