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.
Original language | English (US) |
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Pages (from-to) | 1015-1024 |
Number of pages | 10 |
Journal | Leukemia |
Volume | 36 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2022 |
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research