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.

Tasquinimod Modulates Suppressive Myeloid Cells and Enhances Cancer Immunotherapies in Murine Models

“…Tracking of superantigen-reactive T cells by TCR-Vβ expression demonstrated increased and prolonged presence of TTS-activated CD8 + T cells in tumors following tasquinimod co-treatment, further supporting the induction of a less immunosuppressive environment. A similar increase in tumor-infiltrating CTLs in B16 tumors was reported recently following TTS therapy in combination with anti-CTLA-4 checkpoint blockade [40]. …”

Cytotoxic T Lymphocyte Antigen-4 Down-Regulates T Helper 1 Cells by Increasing Expression of Signal Transducer and Activator of Transcription 3 in Acute Graft-versus-Host Disease

“…As the costimulatory molecule of T cells, CTLA-4 is the second signal, which mainly regulates T cell activation. CTLA-4 also has been documented to play an important role in the progress of anti-tumor [8][9][10] and anti-infection [11][12][13] responses, as well as some autoimmune diseases, including polymyositis [14] and systemic lupus erythematosus [15].…”

Modulating Co-Stimulation During Antigen Presentation to Enhance Cancer Immunotherapy

“…Interestingly, CTLA-4 blockade can also be combined with other immunotherapy approaches such as inhibition of inhibitory co-stimulation [178], enhancement of activatory co-stimulation [179, 180], cytokine treatments [181] or superantigens [182]. These approaches turn the balance towards effector T cell activities instead of Tregs [183].…”