TY - JOUR T1 - CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-019-0806-7 VL - 7 IS - 1 SP - 304 AU - Bryan D. Choi AU - Xiaoling Yu AU - Ana P. Castano AU - Henia Darr AU - Daniel B. Henderson AU - Amanda A. Bouffard AU - Rebecca C. Larson AU - Irene Scarfò AU - Stefanie R. Bailey AU - Genevieve M. Gerhard AU - Matthew J. Frigault AU - Mark B. Leick AU - Andrea Schmidts AU - Jason G. Sagert AU - William T. Curry AU - Bob S. Carter AU - Marcela V. Maus Y1 - 2019/12/01 UR - http://jitc.bmj.com/content/7/1/304.abstract N2 - 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.Abbreviations:B2M beta-2 microglobulinCARchimeric antigen receptorCNScentral nervous systemCSFcerebrospinal fluidGBMglioblastomaGVHDgraft-versus-host diseasePD-L1programmed cell death ligand 1TALENTAL effector nucleaseTCRT-cell receptorTRACT-cell receptor alpha constantZFNzinc finger nuclease ER -