A drawback of combining different immune checkpoint inhibitors is their unspecific mode of action involving “off-site” activation of T cells, which gives rise to undesired side effects . Therefore, we established a novel combination therapy making use of only one immune checkpoint inhibitor. This approach allows the activity of Ipilimumab to be targeted to T cells that strongly express CTLA-4 as a consequence of their specific stimulation in the presence of tumor cells. The tumor-specific T-cell activation is secured by trifunctional bispecific antibodies (trAbs), which selectively redirect T cells to tumor cells by virtue of two different binding arms recognizing CD3 and a tumor-associated antigen (TAA), respectively. Additionally, the intact Fc region of trAbs recruits and stimulates accessory cells such as dendritic cells (DCs) or macrophages via activating Fc receptors [13, 14]. These cells provide additional stimuli to T cells, take up tumor cell debris and present tumor-derived peptides to the immune system [15, 16]. Thus, trAbs not only lead to T cell-dependent tumor destruction, but also induce a long-lasting tumor-specific immunologic memory [16–18]. The role of the intact Fc region was established by experiments using Fc blocking or Fc-devoid antibody constructs [15–17, 19]. TrAbs are already in clinical use. Catumaxomab, for example, which binds to the TAA epithelial cell adhesion molecule (EpCAM), has been approved for the treatment of malignant ascites . Other trAb constructs are investigated in clinical studies.