Reprogramming human T cell function and specificity with non-viral genome targeting
Open accessPublished version of a preprint
Abstract
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes 1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites 3,4. 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 repair 5,6. 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.
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In a Phase I clinical trial, an autologous bispecific CD19/CD22-targeted CAR T cell therapy was manufactured using the FasT CAR platform, reducing cell culture time to less than 24 hours.
“For a Phase I clinical trial, researchers manufactured an autologous, bispecific CD19/CD22-targeted CAR T cell therapy using the FasT CAR platform, reducing cell culture time to less than 24 hours (117,118).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [118]
The Abstract (page unavailable) describes preclinical engineering of NY-ESO-1-targeted TCR cells, not a Phase I trial of bispecific CD19/CD22 CAR T cells. The Methods (Primary human T cell culture, page unavailable) specify two days of stimulation before electroporation, and the Abstract reports ten days of expansion—not cell culture lasting less than 24 hours. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn ten adolescent and adult patients with CD19+ relapsed/refractory B-ALL who received CD19 FasT CAR T cells, 10/10 (100%) achieved CR on day 15 after infusion, with only one patient experiencing CRS.
“On day 15 after cell infusion, 10/10 (100%) patients achieved CR, with only one patient experiencing CRS (118).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [118]
The Abstract describes NY-ESO-1 TCR-engineered cells reducing tumour burden in treated animals, and Extended Data Figure 10 describes a mouse melanoma model; neither reports outcomes for patients receiving CD19 FasT CAR T cells. Searches for the day-15 10/10 complete-remission result and cytokine release syndrome found no passage addressing those claims. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredMultiple barcoded templates introduced into the same cell could complicate interpretation of each one's effects.
“In addition, multiple barcoded templates introduced in the same cell could complicate interpretation of each one’s effects (Feldman et al., 2018; Roth et al., 2018).”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Roth et al., 2018
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- Authors
- Roth, T. L., Puig-Saus, C., Yu, R., Shifrut, E., Carnevale, J., Li, P. J., Hiatt, J., Saco, J., Krystofinski, P., Li, H., Tobin, V., Nguyen, D. N., Lee, M. R., Putnam, A. L., Ferris, A. L., Chen, J. W., Schickel, J.-N., Pellerin, L., Carmody, D., Alkorta-Aranburu, G., del Gaudio, D., Matsumoto, H., Morell, M., Mao, Y., Cho, M., Quadros, R. M., Gurumurthy, C. B., Smith, B., Haugwitz, M., Hughes, S. H., Weissman, J. S., Schumann, K., Esensten, J. H., May, A. P., Ashworth, A., Kupfer, G. M., Greeley, S. A. W., Bacchetta, R., Meffre, E., Roncarolo, M. G., Romberg, N., Herold, K. C., Ribas, A., Leonetti, M. D., & Marson, A.
- Affiliations
- University of California, San Francisco (US)
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- National Cancer Institute (US)
- Yale University (US)
- Stanford Medicine (US)
- University of Chicago (US)
- Takara (United States) (US)
- Chan Zuckerberg Biohub San Francisco (US)
- University of Nebraska Medical Center (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Marson, Alexander
- ORCID
- Roth, Theodore L.
- Puig-Saus, Cristina
- Shifrut, Eric
- Carnevale, Julia
- Li, P. Jonathan
- Hiatt, Joseph
- Saco, Justin
- Krystofinski, Paige
- Li, Han
- Tobin, Victoria
- Nguyen, David N.
- Putnam, Amy L.
- Chen, Jeff W.
- Schickel, Jean-Nicolas
- Pellerin, Laurence
- Carmody, David
- Mao, Ying
- Quadros, Rolen M.
- Gurumurthy, Channabasavaiah B.
- Hughes, Stephen H.
- Weissman, Jonathan S.
- Schumann, Kathrin
- Esensten, Jonathan H.
- May, Andrew P.
- Ashworth, Alan
- Kupfer, Gary M.
- Greeley, Siri Atma W.
- Bacchetta, Rosa
- Meffre, Eric
- Roncarolo, Maria Grazia
- Romberg, Neil
- Herold, Kevan C.
- Ribas, Antoni
- Leonetti, Manuel D.
- Marson, Alexander
- Venue
- Nature
- Published
- 2018-07
- Volume
- 559
- Issue
- 7714
- Pages
- 405-409
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6239417
- OpenAlex
- W2818540548
- Cited by
- 839
- References
- 32
- Citations by year
- 2026: 89 · 2025: 82 · 2024: 93 · 2023: 110 · 2022: 116 · 2021: 128 · 2020: 100 · 2019: 98 · 2018: 21 · 2017: 1
- FWCI
- 30.70
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Burroughs Wellcome Fund
- W. M. Keck Foundation
- Jeffrey Modell Foundation
- Sanofi
- Gilead Sciences
- Parker Institute for Cancer Immunotherapy (P30 DK063720, R35 CA197633)
- Multiple Sclerosis Society
- National Institutes of Health (1s10od021822-01, DK020595, DK063720, NIH P30 DK063720)
- University of California, San Francisco (T32 DK007418, 1S10OD021822-01, T32GM007618, P30DK063720, DK063720)
- Juno Therapeutics
- National Cancer Institute (CA197633, T32CA108462, P30CA082103, R35CA197633)
- National Institute of General Medical Sciences (P50GM082250, T32GM007618)
- National Institute of Allergy and Infectious Diseases (T32AI007334, K23AI115001, L40 AI140341, T32AI007641)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK111914, K23DK094866, P30DK063720, T32DK007418, P30DK020595)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- CRISPR/Cas9 genome editing, T cell engineering, cancer immunotherapy, homology-directed repair, T cell reprogramming
- MeSH terms
- Gene Editing, Animals, Cells, Cultured, Humans, Male, Neoplasm Transplantation, Receptors, Antigen, T-Cell, T-Lymphocytes, Protein Engineering, Autoimmunity, Genome, Human, Mice, Interleukin-2 Receptor alpha Subunit, CRISPR-Cas Systems, Cellular Reprogramming
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