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Wang, Xiuli; Dong, Zhenyuan; Awuah, Dennis; Chang, Wen-Chung; Cheng, Wesley A; Vyas, Vibhuti; Cha, Soung-Chul; Anderson, Aaron J; Zhang, Tiantian; Wang, Zhe; Szymura, Szymon J; Kuang, Benjamin Z; Clark, Mary C; Aldoss, Ibrahim; Forman, Stephen J; Kwak, Larry W; Qin, Hong
Leukemia, 04/2022, Volume: 36, Issue: 4Journal Article
Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent antitumor effects in B-cell malignancies including acute lymphoblastic leukemia (ALL), but antigen loss remains the major cause of treatment failure. To mitigate antigen escape and potentially improve the durability of remission, we developed a dual-targeting approach using an optimized, bispecific CAR construct that targets both CD19 and BAFF-R. CD19/BAFF-R dual CAR T cells exhibited antigen-specific cytokine release, degranulation, and cytotoxicity against both CD19-/- and BAFF-R-/- variant human ALL cells in vitro. Immunodeficient mice engrafted with mixed CD19-/- and BAFF-R-/- variant ALL cells and treated with a single dose of CD19/BAFF-R dual CAR T cells experienced complete eradication of both CD19-/- and BAFF-R-/- ALL variants, whereas mice treated with monospecific CD19 or BAFF-R CAR T cells succumbed to outgrowths of CD19-/BAFF-R+ or CD19+/BAFF-R- tumors, respectively. Further, CD19/BAFF-R dual CAR T cells showed prolonged in vivo persistence, raising the possibility that these cells may have the potential to promote durable remissions. Together, our data support clinical translation of BAFF-R/CD19 dual CAR T cells to treat ALL.
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