Development of Chimeric Antigen Receptor-Modified NK Cells for the Immunotherapy of Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy with a poor prognosis and limited therapeutic options. ATL cells exhibit aberrant surface glycosylation patterns resulting from dysregulated glycosyltransferase expression, representing a potentially tumor-specific therapeutic target. We previously isolated an ATL-specific single-chain variable fragment (scFv), S1TSCFR3-1, that selectively binds to ATL cell surface glycans. In this study, we engineered natural killer (NK) cells to express a chimeric antigen receptor (CAR) incorporating S1TSCFR3-1 and evaluated their therapeutic potential against ATL. In vitro, CAR-NK cells exhibited dose-dependent cytotoxicity against ATL cell lines, mediated primarily through enhanced granzyme B production, whereas no augmentation of cytotoxic activity was observed against non-ATL cell lines. S1TSCFR3-1 binding was detected in PBMCs from 3 of 7 ATL patients, and CAR-NK cells demonstrated significant cytotoxicity against PBMCs from a binding-positive patient. In a xenograft mouse model, administration of irradiated CAR-NK cells partially suppressed tumor burden as evidenced by reduced serum hsIL-2R levels, although survival benefit did not reach statistical significance. These findings suggest that CAR-NK cell therapy targeting ATL-associated aberrant glycan epitopes represents a potentially valuable therapeutic approach warranting further investigation.