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

Article · Levi J. Rupp, Kathrin Schumann, Kole T. Roybal, Rachel E. Gate, Chun Ye, Wendell A. Lim, Alexander Marson

- Archive id: doi:10.1038/s41598-017-00462-8
- Published: 2017-04-03
- Venue: Scientific Reports
- DOI: https://doi.org/10.1038/s41598-017-00462-8
- PMID: 28389661
- Citations: 757
- Source URL: https://doi.org/10.1038/s41598-017-00462-8
- PDF: https://www.nature.com/articles/s41598-017-00462-8.pdf
- Provenance: openalex

## Abstract

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.

_Abstract reproduced under CC-BY (publisher license, via OpenAlex)._

Topics: [CRISPR & Gene-Editing Therapies](https://space-kitty.com/topics/gene-editing-therapies), [Cancer Immunotherapy](https://space-kitty.com/topics/cancer-immunotherapy)

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