355. Specific Lysis of Multiple Myeloma Cells by T-Cells Engineered To Express a Chimeric Immune Receptor Targeting WUE-Antigen

Abstract

Multiple myeloma (MM) is the second most common hematological malignancies with an incidence of 4.1/100.000 per year. Disease control can be achieved by high-dose chemotherapy followed by autologous stem transplantation but relapse occurs in over 90% of all patients. Thus the development of novel concepts for eradication of minimal residual disease are highly warranted. Adoptive immunotherapy represent an attractive approach for augmenting tumor immunity and may be achieved by genetically modifying T-cells with an MM-specific chimeric immunoreceptor targeting the cell-surface antigen Wue-1. In contrast to healthy plasma cells Wue-1 is homogenously over expressed by primary MM cells and is not detected in other hematopoietic and nonhematopoietic tissues. An antibody-derived single-chain variable domains (scFvs) was fused with the CD3-ζ intracellular signaling domain. Primary CD4+ and CD8+ T-cells were genetically modified by retroviral-mediated gene-transfer with the constructed receptor and T-cell clones established from both genetically modified CD4+ and CD8+ T-cells. Cr-release assays performed with the generated CD8+ T-cells utilizing Wue-antigen (Wue-Ag) expressing MM cell lines as targets resulted into 72% specific lysis of the MM cells (E/T 5:1). In contrast non-Wue-Ag expressing targets were not recognized. Both CD4+ and CD8+ T-cells modified T-cells produced cytokines in responses to Wue-Ag expressing MM cell lines. Cytokine production could be blocked by preincubating target cell with the anti-Wue antibody, demonstrating the specific stimulation of modified T-cell by the interaction of the expressed chimeric receptor and Wue-Ag. Furthermore utilizing freshly isolated CD138+ cells from MM patients as stimulators resulted in specific production of cytokines and specific lysis by the modified T-cells, demonstrating that primary MM cells despite escape mechanism can be eradicated. In summary, CD4+ and CD8+ T-cells can be render to be highly specific for MM cells by expression of a chimeric immunoreceptors targeting Wue-surface Ag and therefore represents an attractive approach targeting relapsed multiple myeloma.