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, Rachel E. Gate, Chun Jimmie Ye, Wendell A. Lim, A. Marson. Scientific Reports, 2016

652 citations recorded by the source corpus.

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.

Subfields: Biomedical Engineering, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/27ffac41ff676af9dc298997351e23839515638e

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In Biomedical Engineering

1. Christopher S. Hackett
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Citations in the corpus

• CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment (2019, methodology): “In both cases, tumors were eradicated in mouse xenograft models using the IR knockout CAR T cells (138, 139).”
• Recent advances and discoveries on the mechanisms and functions of CAR T cells (2021, positive): “This improves antitumour immunity in vitro and within in vivo models in the presence of PDL1 + tumours 123 .”
• Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, methodology): “169 ) have been used to delete the gene encoding PD-1 ( PD1 ) in CAR T cells.”
• CAR-NK cells: A promising cellular immunotherapy for cancer (2020, background): “[109] Like T cells, activated NK cells also expressed some T cell immune checkpoint molecules (e.”