Abstract
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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Acknowledgements
The Small Animal Imaging Core is supported by the National Cancer Institute of the National Institutes of Health (P30CA033572); Toni Stephenson Lymphoma Center (PI: L.W.K.); Leukemia and Lymphoma Society Mantle cell lymphoma Research Initiative (SCOR 7000-18; PI: L.W.K.; Project Leaders: S.J.F.; X.W.; E.L.B.); Department of Defense (CA170783, PI: L.W.K.). Lymphoma SPORE (P50 CA107399-11, PI: S.J.F; L.W.K; Project leaders: X.W.; R.N.).
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L.W.K., S.J.F., X.W., I.A., and H.Q. designed and directed the study, analyzed and organized the data, and wrote the manuscript. W.C.C., V.V., D.A. designed the vectors and produced lentivirus. D.A., Z.D., S.C., T.Z., Z.W., S.S., B.K., and A.A. performed experimental work in mice and immune assays. M.C.C. and W.A.C. reviewed and edited the manuscript. All authors read and approved the final version.
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Sources of support include the National Cancer Institute of the National Institutes of Health (P30CA033572) supporting the Small Animal Imaging Core, National Cancer Institute Lymphoma SPORE (PI: L.W.K.), Leukemia and Lymphoma Society Mantle cell lymphoma Research Initiative (SCOR 7000-18; PI: L.W.K.; Project Leaders: S.J.F.; X.W.), Department of Defense (CA170783, PI: L.W.K.). X.W. is a paid consultant for Pepromene Bio, Inc.; L.W.K. and H.Q. are paid consultants and have equity in Pepromene Bio, Inc. The other authors report no disclosures.
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Wang, X., Dong, Z., Awuah, D. et al. CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia. Leukemia 36, 1015–1024 (2022). https://doi.org/10.1038/s41375-021-01477-x
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DOI: https://doi.org/10.1038/s41375-021-01477-x
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