Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors

The 4-1BB glycoprotein is a member of the tumor necrosis factor receptor superfamily(1-4) and binds to a high-affinity ligand (4-1BBL) expressed on several antigen-presenting cells such as macrophages and activated B cells(5,6). Expression of 4-1BB is restricted to primed CD4(+) and CD8(+) T cells(7), and 4-1BB signaling either by binding to 4-1BBL or by antibody ligation delivers a dual mitogenic signal for T-cell activation and growth(8-12). These observations suggest an important role for 4-1BB in the amplification of T cell-mediated immune responses. We now show that administration of anti-4-1BB monoclonal antibodies can eradicate established large tumors in mice, including the poorly immunogenic Ag104A sarcoma and the highly tumorigenic P815 masto cytoma. The immune response induced by anti-4-1BB monoclonal antibodies is mediated by both CD8(+) and CD4(+) T cells and is accompanied by a marked augmentation of tumor-selective cytolytic T-cell activity. Our data suggest that a similar approach may be efficacious for immunotherapy of human cancer.