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Adult allogeneic CD4+ and CD8+ enriched T cells transduced with an anti-CD19 chimeric antigen receptor (CAR) that is site-specific integrated into the cellular genome.
Adult allogeneic CD4+ and CD8+ enriched T cells, gene edited through the electroporation of homing endonuclease mRNA, which is translated into endonuclease protein that introduces a doublestranded DNA break in exon 1 of the endogenous T cell receptor alpha constant (TRAC) locus. Cells are subsequently transduced with a recombinant nonreplicating adeno-associated virus type 6 (rAAV6) vector, encoding an anti-CD19 CAR transgene consisting of a murine CD19-specific scFv (clone FMC63), a CD8 hinge/transmembrane domain, a novel 6 (N6) co-stimulatory domain and CD3 zeta signaling domain, under the control of the synthetic promoter JeT and the SV40 poly(A) signal. CAR transgene integration is achieved via homology directed recombination at the endonuclease target site (exon 1 of TRAC). Depletion of CD3+ cells is performed on the transduced cells to remove cells with functional endogenous T cell receptor (TCR). The substance is a mixture of non-effector (naive, stem cell memory, central memory) (CCR7+) and effector memory and effector (CCR7-) CD4+ and CD8+ T cells with generally ≥99% T cell receptor knockout, and ≥40% anti-CD19 CAR knock-in. Activation of the cells is accompanied in vitro by release of IFNγ, IL-2, IL-6, and TNFα in an antigen-dependent manner.

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