ANTIBODY-TARGETED SUPERANTIGENS ARE POTENT INDUCERS OF TUMOR-INFILTRATING T-LYMPHOCYTES IN-VIVO

Recruitment of antigen-specific tumor-infiltrating lymphocytes (TILs) is a major goal for immunotherapy of malignant tumors. We now describe that T-cell-activating superantigens targeted to a tumor by monoclonal antibodies induced large numbers of pseudospecific TILs and eradication of micrometastases, As a model for tumor micrometastases, syngeneic B16 melanoma cells transfected with the human colon carcinoma antigen C215 were injected intravenously into C57BL/6 mice and therapy with an anti-C215 Fab fragment-staphylococcal enterotoxin A (C215Fab-SEA) fusion protein reacting with the C215 antigen was initiated when visible lung metastases were established, More than 90% reduction of the number of lung metastases was observed when mice carrying 5-day-old established lung metastases were treated with C215Fab-SEA. The antitumor effect of C215Fab-SEA was shown to be T-cell-dependent since no therapeutic effect was seen in T-cell-deficient nude mice, Depletion of T-cell subsets by injection of monoclonal antibody demonstrated that CD8(+) cells were the most prominent effector cells although some contribution from CD4(+) cells was also noted. C215Fab-SEA treatment induced massive tumor infiltration of CD4(+) and CD8(+) T cells, while only scattered T cells were observed in untreated tumors, SEA treatment alone induced a slight general inflammatory response in the lung parenchyme, but no specific accumulation of T cells was seen in the tumor. TILs induced by C215Fab-SEA were mainly CD8(+) but a substantial number of CD4(+) cells were also present, Immunohistochemical analysis showed strong production of the tumorcidal cytokines tumor necrosis factor alpha and interferon gamma in the tumor, Thus, the C215Fab-SEA fusion protein targets effector T lymphocytes to established tumors in vivo and provokes a strong local antitumor immune response.