Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 7, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40425-019-0806-7
Keywords
CRISPR-Cas systems; Receptors; chimeric antigen; EGFRvIII; Glioblastoma
Categories
Funding
- National Institutes of Health [R25NS065743]
- Neurosurgery Research & Education Foundation
- B*Cured Research Fellowship Grant
- Society for Immunotherapy of Cancer-AstraZeneca Postdoctoral Cancer Immunotherapy in Combination Therapies Clinical Fellowship
- Damon Runyon-Rachleff Innovation Award
- Stand Up to Cancer
- CRISPR Therapeutics
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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.
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