CAR T
Published on May 09, 2024
Upregulation CD80/86 in DLBCL and switch CAR/CCR T cells
by Cell Reports Medicine
Prinz LF, Riet T, Neureuther DF, et al. An Anti-CD19/CTLA-4 Switch Improves Efficacy and Selectivity of CAR T Cells Targeting CD80/86-Upregulated DLBCL. Cell Reports Medicine. 2024; 5 (2) (doi: 10.1016/j.xcrm.2024.101421).
A novel co-targeting design promises to heighten the effects of chimeric antigen receptor (CAR) T-cell activity in certain B-cell lymphoma patients, a population that can benefit from CAR treatment but may not realize durable remission. Based on biopsies, researchers learned that expression of CD80 and/or CD86, both immune checkpoint ligands, is upregulated in the tumor tissue of patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) before and after CAR T therapy. The discovery informed development of a CAR chimeric checkpoint receptor (CAR/CCR) construct capable of distinguishing healthy B cells from tumor cells in the setting of DLBCL. Pairing an anti-CD19 CAR with a CTLA-4 domain binding to CD80/86 and housing a 4-1BB co-activating signaling unit results in full activation of CAR/CCR T cells only when they bind to both antigens. Because binding to CD19 alone is not adequate to trigger this activity, on-target off-tumor activity is curtailed both in vitro and in vivo. In xenograft murine models, switch CAR/CCR T cells demonstrated higher efficacy, superior long-term activity, and better selectivity than conventional CAR T cells, making the approach an attractive candidate for additional translational investigation.
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