Our purpose is to make use of a novel means of generating immunogenic tumor variants for the immunotherapy of metastasis. The animal model described is one which attempts to mimic the clinical situation, where metastasis is the major cause of death. Our protocols include surgical removal of the primary tumor followed by treatment with cyclophosphamide to inhibit putative suppressor T cells. This is followed by adoptive immunization with syngeneic lymphocytes activated with immunogenic clones derived from the parent tumor by mutagen or UV light treatment. These immunogenic clones generate allogeneic-like cytotoxic T cell responses which protect against parent tumor challenge in vivo. Preliminary data have demonstrated that adoptive immunotherapy can 'cure' as many as 60% of animals bearing one of the most aggressive metastatic murine tumors known. In addition, we have early evidence that active immunization of animals with established metastasis with viable immunogenic clones, may also be an effective therapeutic modality. We plan to further assess the use of IL-2 in combination with adoptive or active immunotherapy for the treatment of established metastasis, an attempt will also be made to assess the usefullness of adoptive and/or active immunization in conjunction with non-specific macrophage activation using MTP-PE. Experiments designed to define at least in part, the nature of the mutagen or UV induced antigen will also be performed.
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