Molecular therapy : the journal of the American Society of Gene TherapyFeb 27, 2017

Inserting a CD19 CAR into the TCR Alpha Chain Gene Simplifies Production of Gene-Edited Donor CAR T Cells

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 21, 2026

Abstract

Allogeneic CAR T cells targeting CD19 were generated through a novel gene editing strategy that eliminates the endogenous T cell receptor.

The new method involves inserting a CAR transgene directly into the native T cell receptor locus using an engineered homing endonuclease.
Anti-CD19 CAR T cells produced via this approach do not express the endogenous T cell receptor.
These CAR T cells exhibit potent effector functions in laboratory tests.
In a mouse model, the CAR T cells effectively cleared CD19-positive tumors.

Simplified

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19hematological malignancies, including durable complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells. Alternatively, T cells from a healthy donor can be used to produce an allogeneic CAR T therapy, provided the cells are rendered incapable of eliciting graft versus host disease (GvHD). One approach to the production of these cells is gene editing to eliminate expression of the endogenous T cell receptor (TCR). Here we report a streamlined strategy for generating allogeneic CAR T cells by targeting the insertion of a CAR transgene directly into the native TCR locus using an engineered homing endonuclease and an AAV donor template. We demonstrate that anti-CD19 CAR T cells produced in this manner do not express the endogenous TCR, exhibit potent effector functions in vitro, and mediate clearance of CD19tumors in an in vivo mouse model. + +

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Inserting a CD19 CAR into the TCR Alpha Chain Gene Simplifies Production of Gene-Edited Donor CAR T Cells

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