| Literature DB >> 32029687 |
Edward A Stadtmauer1,2, Joseph A Fraietta2,3,4,5,6, Simon F Lacey5,6, Carl H June7,3,5,6, Megan M Davis5,6, Adam D Cohen8,2, Kristy L Weber2,9, Eric Lancaster10, Patricia A Mangan8, Irina Kulikovskaya5, Minnal Gupta5, Fang Chen5, Lifeng Tian5, Vanessa E Gonzalez5, Jun Xu5, In-Young Jung4,5, J Joseph Melenhorst3,5,6, Gabriela Plesa5, Joanne Shea5, Tina Matlawski5, Amanda Cervini5, Avery L Gaymon5, Stephanie Desjardins5, Anne Lamontagne5, January Salas-Mckee5, Andrew Fesnak5,6, Donald L Siegel5,6, Bruce L Levine5,6, Julie K Jadlowsky5, Regina M Young5, Anne Chew5, Wei-Ting Hwang11, Elizabeth O Hexner8,2, Beatriz M Carreno3,5,6, Christopher L Nobles4, Frederic D Bushman4, Kevin R Parker12, Yanyan Qi13, Ansuman T Satpathy12,13, Howard Y Chang12,14, Yangbing Zhao5,6.
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.Entities:
Mesh：
Substances：
Year: 2020 PMID： 32029687 DOI： 10.1126/science.aba7365
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728