In an attempt to endow mAb-mediated blockade of CTLA-4 with increased specificity for tumor-reactive T cells, we examined whether trAb-induced T-cell activation and neutralization of the concomitant CTLA-4 upregulation on T cells cooperate with regard to enhanced tumor rejection and induction of an immunologic memory. A model tumor used in this paper is the B16F0-derived melanoma B78-D14, which is engineered to express GD2 . This ganglioside is a promising antigen for targeting small cell lung cancer and malignancies of neuroectodermal origin such as neuroblastoma, glioma, sarcoma or melanoma in humans [22–24]. We also included the more immunogenic melanoma B16-EpCAM , which expresses the antigen recognized by the clinically relevant trAb Catumaxomab . The constructs Surek [17, 19, 25, 26] and BiLu  served as surrogate trAbs cross-linking GD2 or EpCAM, respectively, with the CD3 receptor on murine T cells.