Details

Autor(en) / Beteiligte

• MacLeod, Daniel T.
• Antony, Jeyaraj
• Martin, Aaron J.
• Moser, Rachel J.
• Hekele, Armin
• Wetzel, Keith J.
• Brown, Audrey E.
• Triggiano, Melissa A.
• Hux, Jo Ann
• Pham, Christina D.
• Bartsevich, Victor V.
• Turner, Caitlin A.
• Lape, Janel
• Kirkland, Samantha
• Beard, Clayton W.
• Smith, Jeff
• Hirsch, Matthew L.
• Nicholson, Michael G.
• Jantz, Derek
• McCreedy, Bruce

Titel

Integration of a CD19 CAR into the TCR Alpha Chain Locus Streamlines Production of Allogeneic Gene-Edited CAR T Cells

Ist Teil von

• Molecular therapy, 2017-04, Vol.25 (4), p.949-961

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19+ hematological 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 CD19+ tumors in an in vivo mouse model. MacLeod and colleagues use a homing endonuclease and an AAV vector to insert an anti-CD19 CAR into the TRAC gene to create universal allogeneic CAR T cells. Targeted insertion of a CAR transgene may allow the generation of more homogeneous CAR T cell products with more predictable safety and efficacy profiles.