51. CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma
- Author
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Bryan D. Choi, Xiaoling Yu, Ana P. Castano, Henia Darr, Daniel B. Henderson, Amanda A. Bouffard, Rebecca C. Larson, Irene Scarfò, Stefanie R. Bailey, Genevieve M. Gerhard, Matthew J. Frigault, Mark B. Leick, Andrea Schmidts, Jason G. Sagert, William T. Curry, Bob S. Carter, and Marcela V. Maus
- Subjects
CRISPR-Cas systems ,Receptors, chimeric antigen ,EGFRvIII ,Glioblastoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - 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.
- Published
- 2019
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