An experimental tumor system has been developed in which: (a) the molecular nature and genetic origin of unique tumor-specific transplantation antigens have been characterized, (b) syngeneic tumor-specific monoclonal antibodies and T cell lines have been generated, (c) tumor variants and gene transfectants carrying various antigenic components have been isolated, (d) specific changes of the tumor-specific antigenicity clearly correlate with malignant behavior, and (e) a large number of control tumors is available. The well-characterized tumor model will be used to develop several new complementary approaches for immunological manipulation of cancer cells in tumor-bearing individuals. This long-term objective will be achieved by (a) stimulating clonotypes or classes of effector cells previously unrecruited, suppressed or reactive with different tumor antigens, (b) providing an appropriate strong """"""""second signal"""""""" or (c) improving antigen presentation. To elicit previously unrecruited T cells, one approach will be to immunize tumor cells whose level of MHC class I expression is either drastically increased by gamma interferon treatment, or decreased by selection of class I-deficient variants. In a second complementary approach, idiotypic and anti-idiotypic antibodies and/or cells will be used to stimulate complementary clones of tumor-specific effector T cells. To elicit a """"""""second signal"""""""" which helps an immune response to weak tumor-specific antigens without mutagenizing or derivatizing them, tumor cells will be transfected with allogeneic class I genes. Tumor cells will also be transfected with class II genes which may endow the tumor cells with certain antigen-presenting function and thus increase the immune response to the cancer cells. Of course, new tumor variants may escape the augmented immunity resulting from these immune manipulations, and the phenotypic alteration of these variants will indicate the relevant destruction mechanism operating. Once the above approaches have been made optimal using highly immunogenic tumors, the procedures will be adapted to more aggressive or even metastatic variants of the same tumor or poorly immunogenic spontaneous tumors.
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