Journal
SCIENCE
Volume 367, Issue 6481, Pages 1001-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aba7365
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Funding
- National Institutes of Health [2R01CA120409]
- Alliance for Cancer Gene Therapy Investigator's Award
- NCI [P01 CA214278, U54 CA24711]
- NIA [U01 AG066100]
- NSF Engineering Research Center for Cell Manufacturing Technologies Seed Grant
- Abramson Cancer Center Emerging Cancer Informatics Center of Excellence Award
- Parker Institute for Cancer Immunotherapy and Tmunity Therapeutics
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CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCR alpha (TRAC) and TCR beta (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.
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