{"id":"doi:10.1038/s41598-017-00462-8","kind":"article","title":"CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells","authors":["Levi J. Rupp","Kathrin Schumann","Kole T. Roybal","Rachel E. Gate","Chun Ye","Wendell A. Lim","Alexander Marson"],"author_count":7,"year":2017,"published":"2017-04-03","venue":"Scientific Reports","cited_by":757,"doi":"10.1038/s41598-017-00462-8","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41598-017-00462-8","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41598-017-00462-8","updated":null,"pmid":"28389661","pmcid":null,"openalex_id":"W2604982880","pdf_url":"https://www.nature.com/articles/s41598-017-00462-8.pdf","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_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["CAR-T cell therapy research"],"details":null,"provenance":"openalex","attribution":"Abstract of \"CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells\" by Levi J. Rupp, Kathrin Schumann, Kole T. Roybal et al., https://doi.org/10.1038/s41598-017-00462-8, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-editing-therapies","name":"CRISPR & Gene-Editing Therapies","domain_slug":"medicine"},{"slug":"cancer-immunotherapy","name":"Cancer Immunotherapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}