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CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells
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CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells
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Journal Article
CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells
2017
Overview
Immunotherapies with chimeric antigen receptor (CAR) T cells and checkpoint inhibitors (including antibodies that antagonize programmed cell death protein 1 [PD-1]) have both opened new avenues for cancer treatment, but the clinical potential of combined disruption of inhibitory checkpoints and CAR T cell therapy remains incompletely explored. Here we show that programmed death ligand 1 (PD-L1) expression on tumor cells can render human CAR T cells (anti-CD19 4-1BBζ) hypo-functional, resulting in impaired tumor clearance in a sub-cutaneous xenograft model. To overcome this suppressed anti-tumor response, we developed a protocol for combined Cas9 ribonucleoprotein (Cas9 RNP)-mediated gene editing and lentiviral transduction to generate PD-1 deficient anti-CD19 CAR T cells.
Pdcd1
(PD-1) disruption augmented CAR T cell mediated killing of tumor cells
in vitro
and enhanced clearance of PD-L1+ tumor xenografts
in vivo
. This study demonstrates improved therapeutic efficacy of Cas9-edited CAR T cells and highlights the potential of precision genome engineering to enhance next-generation cell therapies.
Publisher
Nature Publishing Group UK,Nature Portfolio
Subject
/ 13/107
/ 13/31
/ 42/41
/ 64/60
/ Animals
/ Antigens, Neoplasm - genetics
/ Antigens, Neoplasm - immunology
/ Female
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Programmed Cell Death 1 Receptor - genetics
/ Programmed Cell Death 1 Receptor - metabolism
/ Receptors, Antigen, T-Cell - genetics
/ Receptors, Antigen, T-Cell - metabolism
/ Science
