Статья

CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells

Levi J. RuppCenter for Systems and Synthetic Biology, University of California San Francisco, San Francisco, 94158, CA, USAKathrin SchumannDepartment of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, 94143, USAKole T. RoybalCenter for Systems and Synthetic Biology, University of California San Francisco, San Francisco, 94158, CA, USARachel E. GateBiological and Medical Informatics Graduate Program, University of California, San Francisco, CA, 94158, USAChun YeDepartment of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California, San Francisco, CA, 94143, USAWendell A. LimCenter for Systems and Synthetic Biology, University of California San Francisco, San Francisco, 94158, CA, USA. [email protected]Alexander MarsonDepartment of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, 94143, USA

2017en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1038/s41598-017-00462-8

Цитирования и источники

Цитирований: 4Использованных источников: 0

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