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

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

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

554 Zitate (Scopus)

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 4-1BB) 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.

OriginalspracheEnglisch
Aufsatznummer737
FachzeitschriftScientific Reports
Jahrgang7
Ausgabenummer1
DOIs
PublikationsstatusVeröffentlicht - 1 Dez. 2017
Extern publiziertJa

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