Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals.

Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4+CD25+Foxp3+ regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge. The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti-glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line). Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling. This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic.

Mitsui J ，Nishikawa H ，Muraoka D ，Wang L ，Noguchi T ，Sato E ，Kondo S ，Allison JP ，Sakaguchi S ，Old LJ ，Kato T ，Shiku H ... -  《-》

Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules.

Takeda K ，Kojima Y ，Uno T ，Hayakawa Y ，Teng MW ，Yoshizawa H ，Yagita H ，Gejyo F ，Okumura K ，Smyth MJ ... -  《-》

Anti-4-1BB monoclonal antibody enhances rejection of large tumor burden by promoting survival but not clonal expansion of tumor-specific CD8+ T cells.

May KF Jr ，Chen L ，Zheng P ，Liu Y ... -  《CANCER RESEARCH》

Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses.

Tuve S ，Chen BM ，Liu Y ，Cheng TL ，Touré P ，Sow PS ，Feng Q ，Kiviat N ，Strauss R ，Ni S ，Li ZY ，Roffler SR ，Lieber A ... -  《CANCER RESEARCH》

Tumor-specific crosslinking of GITR as costimulation for immunotherapy.

Burckhart T ，Thiel M ，Nishikawa H ，Wüest T ，Müller D ，Zippelius A ，Ritter G ，Old L ，Shiku H ，Renner C ... -  《-》