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Background aims. Light chain amyloidosis (AL) is a protein deposition disorder that is a result of a plasma cell dyscrasia, similar to multiple myeloma (MM). Immunotherapy is an attractive approach because of the low burden of disease, but the optimal target for AL is unclear. CS1 and B-cell maturation antigen (BCMA) are two potential targets because they are expressed on normal plasma cells and MM cells. Methods. We performed a prospective study evaluating bone marrow specimens of 20 patients with plasma cell diseases, 10 with AL and 10 with MM. We evaluated the clonal population of plasma cells for BCMA and CS1 expression. We designed a second-generation CS1 chimeric antigen receptor (CAR) construct, comprising a CS1 antigen-specific scFv, shortened hinge region and CD28 costimulatory domain. Purified central memory T cells were activated and transduced with a lentiviral vector encoding the CS1 CAR. Cytotoxicity was evaluated using 51Cr release assays. Five days after tumor inoculation, NSG mice were injected intravenously with CS1 CART cells. Results. Whereas CS 1 is present on the plasma cells of AL patients, we found BCMA expression in AL to be markedly low. CS1 CART cells were cytotoxic against CS1 positive tumor cells and induced durable tumor regressions in mice. Discussion. Our work represents a novel application of CSl-directed CART cells while revealing that BCMA would not be a suitable target. We expect AL to be particularly susceptible to CAR T-cell therapy because of the low tumor burden in the bone marrow. [ABSTRACT FROM AUTHOR]