First-in-Human Trial of Multiplex CRISPR-Cas9 Edited T Cells Shows Safety and Durable Engraftment in Cancer
This landmark phase 1 trial demonstrated the safety and feasibility of multiplex CRISPR-Cas9 gene editing in human T cells for cancer immunotherapy. Researchers deleted endogenous TCR genes and PD-1 in T cells from three patients with refractory cancer, then inserted a cancer-specific NY-ESO-1 TCR transgene. The engineered cells engrafted durably for up to nine months with minimal immunogenicity, and chromosomal translocations decreased over time, establishing a critical proof of concept for CRISPR-based cell therapy in oncology.
The original study
CRISPR-engineered T cells in patients with refractory cancer.
- Authors
- Stadtmauer EA, Fraietta JA, Davis MM, Cohen AD, Weber KL, Lancaster E, et al.
- Journal
- Science (New York, N.Y.)
- Type
- Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
- PMID
- 32029687
Original abstract
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, TCRα (TRAC) and TCRβ (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.