Better late than never! A Promisory Abstract from Nature..

1. nature  
2. letters  
3. article

• Letter
• Published: 11 July 2018

Reprogramming human T cell function and specificity with         non-viral genome targeting

• Theodore L. Roth, 
• Cristina Puig-Saus, 
• […]
• Alexander Marson 

Nature volume 559, pages 405–409 (2018)Cite this article

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Abstract

Decades of work have aimed to genetically reprogram T cells for therapeutic  purposes1,2using recombinant viral vectors, which do not target transgenes to                     specific genomic sites3,4.                                                                                                                           

The need for viral vectors has slowed down research and clinical use as their                                         manufacturing and testing is lengthy and expensive.                                                                

Genome editing brought the promise of specific and efficient insertion of large            transgenes into target cells using homology-directed repair5,6.  

 Here we developed a CRISPR–Cas9 genome-targeting system that does not                        require viral vectors, allowing rapid and efficient insertion of large DNA                      sequences (greater than one kilobase) at specific sites in the genomes of                                                    primary human T cells, while preserving cell viability and function.                                             This permits individual or multiplexed modification of endogenous genes.                               

First, we applied this strategy to correct a pathogenic IL2RA mutation in cells                                          from patients with monogenic autoimmune disease, and demonstrate improved                                    signalling function. Second, we replaced the endogenous T cell receptor                                (TCR) locus with a new TCR that redirected T cells to a cancer antigen.                                        The resulting TCR-engineered T cells specifically recognized tumour antigens                                   and mounted productive anti-tumour cell responses in vitro and in vivo.                                  

Together, these studies provide preclinical evidence that non-viral genome                        targeting can enable rapid and flexible experimental manipulation and                               therapeutic engineering of primary human immune cells.