Combinatorial approaches of cancer immunotherapy have attracted much interest in the past years. Specifically, the simultaneous blockade of different immune checkpoints has been extensively evaluated in translational and clinical studies [8–10]. The rationale is to release the brake imposed to bona fide tumor-reactive T cells by surface molecules like CTLA-4, whose induction is considered as a counter-regulatory mechanism required for self-limitation of any immune response [29, 30]. However, tumor escape may be more effectively counteracted if reagents with different modes of action are combined. Therefore, we nourished the blockade of CTLA-4 with trAbs that specifically redirect T cells to TAAs and activate the T cells in the presence of tumor cells. Thus, the unspecific effect of anti-CTLA-4 is supplemented with an antigen-specific component because after trAb treatment, specifically activated T cells with induced CTLA-4 expression can be further stimulated by anti-CTLA-4 mAbs. As a consequence, the redirection of activated T cells by trAbs could be beneficial for the side-effect profile of checkpoint inhibitors. This is indicated by experiments using an allogeneic transplantation setting, which also inherently bears the danger of tissue damage by uncontrolled T-cell activity. Here, T cells could be redirected away from healthy tissues to the tumor site by trAbs, thereby significantly reducing graft-versus-host-disease .