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      Monotherapeutically nonactive CTLA-4 blockade results in greatly enhanced antitumor effects when combined with tumor-targeted superantigens in a B16 melanoma model.

      Journal of Immunotherapy (Hagerstown, Md. : 1997)
      Animals, Antibodies, Monoclonal, administration & dosage, immunology, Antigens, Neoplasm, Antineoplastic Combined Chemotherapy Protocols, therapeutic use, CTLA-4 Antigen, antagonists & inhibitors, Cell Line, Tumor, Female, Immunoglobulin Fab Fragments, Immunotherapy, Lymphocytes, Tumor-Infiltrating, Melanoma, Experimental, mortality, therapy, Mice, Mice, Inbred C57BL, Recombinant Fusion Proteins, Superantigens, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Regulatory

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          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.

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