title: Monotherapeutically nonactive CTLA-4 blockade results in greatly enhanced antitumor effects when combined with tumor-targeted superantigens in a B16 melanoma model.
abstract: Immunotherapy aiming to block immune suppression with anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies is a recently clinically established strategy to enhance immune driven antitumor activities. To be successful, this approach depends on the existence of a suppressed immune response against the tumor that can be released by the treatment or alternatively needs to be combined with an immune-enhancing therapy. A tumor-targeted superantigen (TTS) fusion protein utilizes the strong T-cell activating property of bacterial superantigens in concert with the tumor cell binding capacity in antitumor Fab-fragments. Our purpose was to investigate the feasibility of combining anti-CTLA-4 with TTS therapy against the poorly immunogenic B16 mouse melanoma tumor transfected with the human tumor-associated antigen EpCAM recognized by the C215 monoclonal antibody. B16-EpCAM tumors growing in the lung were completely insensitive to anti-CTLA-4 monotherapy. C215Fab-SEA treatment of the B16-EpCAM tumors induced strong infiltration and targeting of both CD4(+) and CD8(+) T cells. In parallel, Foxp3(+)CTLA-4(high) regulatory T cells accumulated in the tumors. Combining activation with C215Fab-SEA and anti-CTLA-4 showed greatly enhanced antitumor effects and prolonged long-term survival. In parallel, when the expansion of regulatory T cells was inhibited, the number of specific effector T cells was enhanced and the cytotoxic T-lymphocyte activity was significantly improved. Collectively, these data emphasize the potential of combining cancer treatment using anti-CTLA-4 monoclonal antibodies with T-cell activation and directed killing by TTS therapy.
authors.affiliation: Active Biotech AB, Lund, Sweden. anette.sundstedt@activebiotech.com
authors.forename: Anette
authors.initials: A
authors.lastname: Sundstedt
authors.forename: Mona
authors.initials: M
authors.lastname: Celander
authors.forename: Helena
authors.initials: H
authors.lastname: Eriksson
authors.forename: Marie
authors.initials: M
authors.lastname: Törngren
authors.forename: Gunnar
authors.initials: G
authors.lastname: Hedlund
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; D007140:Immunoglobulin Fab Fragments; D011993:Recombinant Fusion Proteins; D018089:Superantigens