Maqola

CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma

Bryan D. ChoiDepartment of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USAXiaoling YuCellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 3.216, Charlestown, Boston, Massachusetts, 02129, USAAna P. Castaño0000 0004 0386 9924grid.32224.35Cellular Immunotherapy Program, Cancer CenterMassachusetts General Hospital and Harvard Medical School 149 13th Street, Room 3.216, Charlestown 02129 Boston Massachusetts USAHenia DarrDaniel B. HendersonAmanda A. BouffardCenter for Cancer ResearchRebecca C. LarsonCenter for Cancer ResearchIrene ScarfòCellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 3.216, Charlestown, Boston, Massachusetts, 02129, USAStefanie R. Bailey0000 0004 0386 9924grid.32224.35Cellular Immunotherapy Program, Cancer CenterMassachusetts General Hospital and Harvard Medical School 149 13th Street, Room 3.216, Charlestown 02129 Boston Massachusetts USAGenevieve M. Gerhard0000 0004 0386 9924grid.32224.35Cellular Immunotherapy Program, Cancer CenterMassachusetts General Hospital and Harvard Medical School 149 13th Street, Room 3.216, Charlestown 02129 Boston Massachusetts USAMatthew J. Frigault0000 0004 0386 9924grid.32224.35Cellular Immunotherapy Program, Cancer CenterMassachusetts General Hospital and Harvard Medical School 149 13th Street, Room 3.216, Charlestown 02129 Boston Massachusetts USAMark B. Leick0000 0004 0386 9924grid.32224.35Cellular Immunotherapy Program, Cancer CenterMassachusetts General Hospital and Harvard Medical School 149 13th Street, Room 3.216, Charlestown 02129 Boston Massachusetts USAAndrea SchmidtsCellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 3.216, Charlestown, Boston, Massachusetts, 02129, USAJason SagertWilliam T. Curry0000 0004 0386 9924grid.32224.35Department of NeurosurgeryMassachusetts General Hospital and Harvard Medical School Boston Massachusetts USABob S. CarterDepartment of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USAMarcela V. Maus0000 0004 0386 9924grid.32224.35Cellular Immunotherapy Program, Cancer CenterMassachusetts General Hospital and Harvard Medical School 149 13th Street, Room 3.216, Charlestown 02129 Boston Massachusetts USA

2019en

Ochiq kirishOltin

Litsenziya: cc-by

ABI

Annotatsiya

Despite remarkable success in the treatment of hematological malignancies, CAR T-cell therapies for solid tumors have floundered, in large part due to local immune suppression and the effects of prolonged stimulation leading to T-cell dysfunction and exhaustion. One mechanism by which gliomas and other cancers can hamper CAR T cells is through surface expression of inhibitory ligands such as programmed cell death ligand 1 (PD-L1). Using the CRIPSR-Cas9 system, we created universal CAR T cells resistant to PD-1 inhibition through multiplexed gene disruption of endogenous T-cell receptor (TRAC), beta-2 microglobulin (B2M) and PD-1 (PDCD1). Triple gene-edited CAR T cells demonstrated enhanced activity in preclinical glioma models. Prolonged survival in mice bearing intracranial tumors was achieved after intracerebral, but not intravenous administration. CRISPR-Cas9 gene-editing not only provides a potential source of allogeneic, universal donor cells, but also enables simultaneous disruption of checkpoint signaling that otherwise impedes maximal antitumor functionality.

Hali tarjima qilinmagan

Identifikatorlar

DOI: 10.1186/s40425-019-0806-7

Iqtiboslar va manbalar

2 ta iqtibos0 ta foydalanilgan manba