CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma. Issue 1 (14th November 2019)

• Record Type: Journal Article
• Authors: Choi, Bryan D.; Yu, Xiaoling; Castano, Ana P.; Darr, Henia; Henderson, Daniel B.; Bouffard, Amanda A.; Larson, Rebecca C.; Scarfò, Irene; Bailey, Stefanie R.; Gerhard, Genevieve M.; Frigault, Matthew J.; Leick, Mark B.; Schmidts, Andrea; Sagert, Jason G.; Curry, William T.; Carter, Bob S.; Maus, Marcela V.
• Is Part Of: Journal for immunotherapy of cancer. Volume 7:Issue 1(2019)
• Publication Date: 2019-11-14
• Subjects: CRISPR-Cas systems -- Receptors, chimeric antigen -- EGFRvIII -- Glioblastoma; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-019-0806-7
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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.