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

Theodore L. Roth, Cristina Puig-Saus, Ruby Yu, Eric Shifrut, Julia Carnevale, P. Jonathan Li, Joseph Hiatt, Justin Saco, Paige Krystofinski, Han Li, Victoria Tobin, David N. Nguyen, Michael R. Lee, Amy L. Putnam, Andrea L. Ferris, Jeff W. Chen, Jean-Nicolas Schickel, Laurence Pellerin, David Carmody, Gorka Alkorta-Aranburu, Daniela del Gaudio, Hiroyuki Matsumoto, Montse Morell, Ying Mao, Min Cho, Rolen M. Quadros, Channabasavaiah B. Gurumurthy, Baz Smith, Michael Haugwitz, Stephen H. Hughes, Jonathan S. Weissman, Kathrin Schumann, Jonathan H. Esensten, Andrew P. May, Alan Ashworth, Gary M. Kupfer, Siri Atma W. Greeley, Rosa Bacchetta, Eric Meffre, Maria Grazia Roncarolo, Neil Romberg, Kevan C. Herold, Antoni Ribas, Manuel D. Leonetti and Alexander Marson ()
Additional contact information
Theodore L. Roth: University of California, San Francisco
Cristina Puig-Saus: University of California at Los Angeles
Ruby Yu: University of California, San Francisco
Eric Shifrut: University of California, San Francisco
Julia Carnevale: University of California, San Francisco
P. Jonathan Li: University of California, San Francisco
Joseph Hiatt: University of California, San Francisco
Justin Saco: University of California at Los Angeles
Paige Krystofinski: University of California at Los Angeles
Han Li: University of California, San Francisco
Victoria Tobin: University of California, San Francisco
David N. Nguyen: University of California, San Francisco
Michael R. Lee: San Francisco
Amy L. Putnam: San Francisco
Andrea L. Ferris: Vector Design and Replication Section, National Cancer Institute
Jeff W. Chen: Yale School of Medicine
Jean-Nicolas Schickel: Yale School of Medicine
Laurence Pellerin: Stanford University
David Carmody: The University of Chicago
Gorka Alkorta-Aranburu: The University of Chicago
Daniela del Gaudio: The University of Chicago
Hiroyuki Matsumoto: Takara Bio USA, Inc
Montse Morell: Takara Bio USA, Inc
Ying Mao: Takara Bio USA, Inc
Min Cho: Chan Zuckerberg Biohub
Rolen M. Quadros: Vice Chancellor for Research Office, University of Nebraska Medical Center
Channabasavaiah B. Gurumurthy: Vice Chancellor for Research Office, University of Nebraska Medical Center
Baz Smith: Takara Bio USA, Inc
Michael Haugwitz: Takara Bio USA, Inc
Stephen H. Hughes: Vector Design and Replication Section, National Cancer Institute
Jonathan S. Weissman: University of California, San Francisco
Kathrin Schumann: University of California, San Francisco
Jonathan H. Esensten: University of California, San Francisco
Andrew P. May: Chan Zuckerberg Biohub
Alan Ashworth: University of California, San Francisco
Gary M. Kupfer: Pathology, Yale School of Medicine
Siri Atma W. Greeley: The University of Chicago
Rosa Bacchetta: Stanford University
Eric Meffre: Yale School of Medicine
Maria Grazia Roncarolo: Stanford University
Neil Romberg: The Children’s Hospital of Philadelphia
Kevan C. Herold: Yale University
Antoni Ribas: University of California at Los Angeles
Manuel D. Leonetti: University of California, San Francisco
Alexander Marson: University of California, San Francisco

Nature, 2018, vol. 559, issue 7714, 405-409

Abstract: Abstract Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using 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.

Date: 2018
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DOI: 10.1038/s41586-018-0326-5

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