T-cell receptor alpha constant locus (TRAC locus) (TRAC)

The T-cell receptor alpha constant (TRAC) locus is a specific genomic region in T-cells that serves as a primary site for the targeted insertion of Chimeric Antigen Receptor (CAR) genes, particularly in the development of therapies for B-cell lymphoma. Unlike traditional viral vectors that integrate randomly into the genome, modern gene-editing technologies like CRISPR/Cas9, TALENs, and ARCUS allow for the precise placement of a CAR transgene into the TRAC locus. This targeted integration offers several therapeutic advantages: it places the CAR under the control of the endogenous TRAC promoter for more physiological and uniform expression, prevents tonic signaling that leads to T-cell exhaustion, and simultaneously knocks out the endogenous T-cell receptor to eliminate the risk of Graft-versus-Host Disease (GvHD) in allogeneic (off-the-shelf) products. By optimizing the genomic environment for CAR expression, targeting the TRAC locus enhances the potency, persistence, and safety profile of CAR-T cell therapies. This approach is currently being utilized in several clinical-stage programs, such as CTX110 and CB-010, to treat relapsed or refractory B-cell malignancies.

Other names

TRAC locusT-cell receptor alpha constant geneTCR alpha constant locusSafe harbor locusAAVS1 locusPDCD1 locusT-cell receptor alpha constant (TRAC)

Site-specific integration of a CAR transgene into the TRAC locus via homology-directed repair (HDR) or non-homologous end joining (NHEJ), which disrupts the endogenous TCR alpha gene to improve CAR expression kinetics and reduce the risk of GvHD in allogeneic T-cell products.