Culturing peripheral blood lymphocytes or tumor infiltrating lymphocytes in the presence of interleukin two (IL-2) results in activation of their ability to kill a variety of tumor cell lines but not freshly isolated normal cells. The immunotherapy of cancer using LAK or TIL cells has given some promising results for a significant fraction of patients with disseminated cancer. The moiety or moieties on the tumor cells which are recognized by the LAK and TIL cells are currently undefined. We propose to study the interaction of human LAK and NK cells with a variety of human cancer cell lines and fresh cells from human tumors. We also propose studies on the recognition of murine tumors by TIL cells. Our proposed methods include; the cloning of LAK cells, the isolation of target cell membrane components and incorporating them into cell-sized synthetic beads (pseudocytes) which specifically block LAK mediated killing of cancer cells and stimulate lymphokine release by NK, LAK, and TIL cells, the partial biochemical purification of the putative receptors(s) using the pseudocyte system as an assay, the development of monoclonal antibodies against the partially purified receptor preparations which interfere with LAK mediated killing of cancer cells, and using the monoclonal antibodies to achieve purification to homogeneity of the receptor(s). In murine systems, we are particularly interested in determining whether TIL recognition of tumors involved MHC restricted antigen fragments that are tumor specific. This project represents a major collaborative effort between a cell membrane biochemist (Grimes) and a clinical immunologist/immunotherapist (Hersh) and is expected to yield new information about the cell biology of tumor immunity and improve the clinical immunotherapy of cancer.
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