Abstract

<div>Abstract<p>Drug-resistant acute lymphoblastic leukemia (ALL) patients do not respond to standard chemotherapy, and an urgent need exists to develop new treatment strategies. Our study exploited the presence of B-cell activating factor receptor (BAFF-R) on the surface of drug-resistant B-ALL cells as a therapeutic target. We used anti–BAFF-R (VAY736), optimized for natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC), to kill drug-resistant ALL cells. VAY736 antibody and NK cell treatments significantly decreased ALL disease burden and provided survival benefit <i>in vivo</i>. However, if the disease was advanced, the ADCC efficacy of NK cells was inhibited by microenvironmental transforming growth factor-beta (TGFβ). Inhibiting TGFβ signaling in NK cells using the TGFβ receptor 1 (R1) inhibitor (EW-7197) significantly enhanced VAY736-induced NK cell–mediated ALL killing. Our results highlight the potential of using a combination of VAY736 antibody with EW-7197 to treat advance-stage, drug-resistant B-ALL patients.</p></div>

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