Multiple myeloma cells are killed by syndecan-1-directed superantigen-activated T cells

Multiple myeloma (MM) is an incurable plasma cell/plasmablast malignancy wi th a great need for innovative treatment strategies. Since experimental imm unotherapy with targeted superantiggens (SAg) proved to be effective in oth er haematopoietic tumours, we investigated whether this would also hold tru e for MM. We used the bacterial SAg Staphylococcus enterotoxin A (SEA),, a potent activator of T cell cytotoxicity by means, of its binding to particu lar T cell receptor VB sequences, on effector cells and MHC class II molecu les on target cells. To eliminate potentially unspecific binding via MHC cl ass II, SEA was point mutated (SEAm). In a second step SEAm was genetically fused to protein A (PA), resulting in a fusion protein (PA-SEAm). This fus ion protein was used together with four different plasma-cell-specific/asso ciated mAbs to direct T cells towards 10 MM target cell lines. Three of the se mAbs-were directed against syndecan-1/CD138, known to be highly expresse d on MM and plasma cells, but absent on other haematopoietic cells. All MM cell lines proved to be, sensitive to SAg-activated T cell killing (15-50% lysis), as measured in a Cr-51-release assay. This effect was clearly media ted via the plasma-cell-reactive antibodies, as control antibodies only con ferred a low background lysis. MM therapy based on targeted SAgs could in t heory be hampered by dysfunctional T cells in MM patients. However, we show that T cells from MM patients and healthy controls responded equally well to activation by SAg.