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 tumours. 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 tumoricidal 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.
Dohlsten
M
M
Pharmacia Oncology Immunology, Lund, Sweden.
Hansson
J
J
Ohlsson
L
L
Litton
M
M
Kalland
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D016207:Cytokines / Q000378:metabolism; D004768:Enterotoxins / Q000276:immunology / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013211:Staphylococcus aureus / Q000276:immunology*; D018089:Superantigens / Q000276:immunology / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D016207:Cytokines; D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal