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Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection
Open accessAbstract
Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Here we show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. We further demonstrate that targeting the CAR to the TRAC locus averts tonic CAR signalling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T-cell differentiation and exhaustion. These findings uncover facets of CAR immunobiology and underscore the potential of CRISPR/Cas9 genome editing to advance immunotherapies.
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“AAV6 homologous donor DNA templates are an efficient way to deliver donor templates for sensitive primary immune cells, including HSPCs and T-Cells15,35–40.”
From A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells (2018) · cites this paper as [39]
Experimental — accuracy not yet measuredIn the citing paper
“More recent work has revealed potential advantages of targeted integrations of antigen receptor genes into defined genomic loci (Eyquem et al., 2017), which can be achieved with programmable nucleases such as CRISPR-Cas9 along with viral or non-viral knock-in templates (Gwiazda et al., 2016; Eyquem et al., 2017; Roth et al., 2018).”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Eyquem et al., 2017
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Self-citationCAR-T cell performance: How to improve their persistence?
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“In addition, to further improve these strategies, the CAR expression could be placed under the control of the TRAC locus, which has been shown to avert the tonic CAR signaling and delay the effector T-cell differentiation and exhaustion (122, 124).”
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“For the expression of CAR in check, CD19-specific CAR is knocked into the TRAC locus of T cells, by which its expression is enhanced and unified under the control of the TCR promoter (37, 38).”
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Zhu, I., Liu, R., Garcia, J. M., Wittsten, A. H., Piraner, D. I., Alavi, J., Israni, D. V., Liu, B., Khalil, A. S., & Roybal, K. T. (2022) · Cell · doi:10.1016/j.cell.2022.03.023 · Cited by 204
“Additional engineering strategies, such as T cell receptor alpha constant (TRAC) knockout (Eyquem et al., 2017), should be considered in these situations where SNIPR-TCR interactions are of concern.”
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“The in vivo analysis focusing on the antitumor effects and persistence of CAR-T cells is essential for creating a clinically effective CAR-T cell medicine because the in vitro cytotoxic activity of CAR-T cells does not always correlate with their in vivo efficacy [39].”
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Self-citationTuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness
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“Taken together, these fi ndings imply that the point mutations we induced within the scFv framework region of CD19.CAR and GD2.CAR have minimal effects on CAR ’ s antigen af fi nity, antigen speci fi city, and safety pro fi le.”
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“CRISPR‐modified cells have been shown to perform well in generally constructed CAR T cells in a mouse model of ALL (96).”
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Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting
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“, 2016) and on editing the endogenous T cell receptor (TCR) of the CAR-modified T cells (Eyquem et al., 2017; Qasim et al., 2017) to mitigate induction of acute graft-versus-host disease (aGVHD), allowing the use of unrelated donor-derived, allogeneic CAR-T cells.”
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“Substantial effort has been invested in developing novel approaches to enhance persistence and expansion of adoptively transferred CAR-T cells (35), including selection of specific T cell subsets (36–38), optimized T cell culture conditions (39, 40), combination therapies (41, 42), genetic modifications and alternativ…”
BackgroundGene correction for SCID-X1 in long-term hematopoietic stem cells
Pavel-Dinu, M., Wiebking, V., Dejene, B. T., Srifa, W., Mantri, S., Nicolas, C. E., Lee, C. M., Bao, G., Kildebeck, E., Punjya, N., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09614-y · Cited by 193
CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies
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“Use of CRISPR/Cas9 could direct incorporation to a specific location in the genome to enhance efficacy, such as the TRAC locus (188).”
BackgroundMaking CAR T Cells a Solid Option for Solid Tumors
Schmidts, A., & Maus, M. V. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02593 · Cited by 193
“, activation in the absence of the cognate antigen (64).”
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“Examples of this category include engineering of immune cells to increase their tumorkilling efficiency by knocking out the immune check-point inhibitor PD1 or by knocking in a chimeric antigen receptor (Eyquem et al., 2017).”
BackgroundLimitations in the Design of Chimeric Antigen Receptors for Cancer Therapy
Stoiber, S., Cadilha, B. L., Benmebarek, M.-R., Lesch, S., Endres, S., & Kobold, S. (2019) · Cells · doi:10.3390/cells8050472 · Cited by 182
“Interestingly, Eyquem and colleagues recently demonstrated that besides baseline CAR expression, the dynamic downregulation and re-expression kinetics following antigen exposure drastically impact the efficacy of CAR T cells [112].”
BackgroundMethodInfluentialNext-Generation CAR T-cell Therapies
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“In addition, allogeneic αβ T cells can be knocked out for the TCR α-chain constant gene ( TRAC ) 102–104 .”
BackgroundCRISPR–Cas: a tool for cancer research and therapeutics
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“Recently, exciting preclinical second-generation genome-edited CAR T cells have been reported in which a combination of Cas9–gRNA and AAV6 was employed to generate a population of cells in which a CD19specific CAR is integrated into the gene encoding the constant region of the TCR alpha chain [39].”
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Allogeneic CAR-T Cells: More than Ease of Access?
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“In China, a clinical trial is recruiting where HD CAR-T cells have both the TRAC and B2M gene disrupted by CRISPR/Cas9 (NCT03166878) although outcome data is not yet available.”
BackgroundMethodInfluentialRasul, M. F., Hussen, B. M., Salihi, A. B., Ismael, B. S., Jalal, P. J., Zanichelli, A., Jamali, E., Baniahmad, A., Ghafouri‐Fard, S., Basiri, A., et al. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01487-4 · Cited by 187
RNA Nanotechnology-Mediated Cancer Immunotherapy
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“Like cancer cells’ highly/over-expressed inhibitory molecules (e.g., PD-L1), some activated T cells also over-express corresponding inhibitory molecules [112, 113], such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and mucin-containing protein 3 (TIM-3).”
BackgroundInfluentialChimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy
Hu, Y., Tian, Z., & Zhang, C. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.125 · Cited by 170
Syk inhibitors in clinical development for hematological malignancies
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Priceman, S. J., Gerdts, E. A., Tilakawardane, D., Kennewick, K. T., Murad, J. P., Park, A. K., Jeang, B., Yamaguchi, Y., Yang, X., Urak, R. Z., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1380764 · Cited by 170
Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating
Hamieh, M., Mansilla‐Soto, J., Rivière, I., & Sadelain, M. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0101 · Cited by 189
Self-citationMinagawa, A., Yoshikawa, T., Yasukawa, M., Hotta, A., Kunitomo, M., Iriguchi, S., Takiguchi, M., Kassai, Y., Imai, E., Yasui, Y., et al. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.10.005 · Cited by 164
Li, W., Qiu, S., Chen, J., Jiang, S., Chen, W., Jiang, J., Wang, F., Si, W., Shu, Y., Wei, P., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.07.011 · Cited by 167
Genetic engineering of T cells for immunotherapy
Ellis, G. I., Sheppard, N. C., & Riley, J. L. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00329-9 · Cited by 170
Salter, A. I., Rajan, A., Kennedy, J. J., Ivey, R. G., Shelby, S. A., Leung, I., Templeton, M. L., Muhunthan, V., Voillet, V., Sommermeyer, D., et al. (2021) · Science Signaling · doi:10.1126/scisignal.abe2606 · Cited by 165
Targeted homology-directed repair in blood stem and progenitor cells with CRISPR nanoformulations
Shahbazi, R., Sghia-Hughes, G., Reid, J. L., Kubek, S., Haworth, K. G., Humbert, O., Kiem, H., & Adair, J. E. (2019) · Nature Materials · doi:10.1038/s41563-019-0385-5 · Cited by 158
Chimeric antigen receptor–modified T cells: CD19 and the road beyond
Salter, A. I., Pont, M. J., & Riddell, S. R. (2018) · Blood · doi:10.1182/blood-2018-01-785840 · Cited by 166
Sachdeva, M., Duchateau, P. N., Depil, S., Poirot, L., & Valton, J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ac119.007558 · Cited by 165
One-step generation of modular CAR-T cells with AAV–Cpf1
Dai, X., Park, J. J.-Y., Du, Y., Kim, H. R., Wang, G., Errami, Y., & Chen, S. (2019) · Nature Methods · doi:10.1038/s41592-019-0329-7 · Cited by 161
“CRISPR/Cas9-mediated TRAC knockin improved CAR-T stability and function 11, 15 .”
InfluentialT cell receptor therapeutics: immunological targeting of the intracellular cancer proteome
Klebanoff, C. A., Chandran, S. S., Baker, B. M., Quezada, S. A., & Ribas, A. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00809-z · Cited by 164
“49,62,63) can be used to disrupt the endogenous TRAC and/or TRBC1/2 loci.”
BackgroundSignaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells
Wu, L., Wei, Q., Brzostek, J., & Gascoigne, N. R. J. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0470-3 · Cited by 164
Engineered Cytokine Signaling to Improve CAR T Cell Effector Function
Bell, M. R., & Gottschalk, S. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.684642 · Cited by 164
Zhang, Q., Hresko, M. E., Picton, L. K., Su, L., Hollander, M. J., Nuñez-Cruz, S., Zhang, Z., Assenmacher, C., Sockolosky, J. T., García, K. C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abg6986 · Cited by 158
Tailoring inorganic nanoadjuvants towards next-generation vaccines
Li, X., Wang, X., & Ito, A. (2018) · Chemical Society Reviews · doi:10.1039/c8cs00028j · Cited by 153
TET2 guards against unchecked BATF3-induced CAR T cell expansion
Jain, N., Zhao, Z., Feucht, J., Koche, R. P., Iyer, A., Dobrin, A., Mansilla‐Soto, J., Yang, J. L., Zhan, Y. A., Lopez, M. A., et al. (2023) · Nature · doi:10.1038/s41586-022-05692-z · Cited by 159
Self-citationEngineered off-the-shelf therapeutic T cells resist host immune rejection
Mo, F., Watanabe, N., McKenna, M. K., Hicks, J. M., Srinivasan, M., Gomes‐Silva, D., Atilla, E., Smith, T. S., Atilla, P. A., Ma, R., et al. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0601-5 · Cited by 155
The potential of activator protein 1 (AP-1) in cancer targeted therapy
Song, D., Lian, Y., & Zhang, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1224892 · Cited by 153
“T cell exhaustion has been regarded as a cause of Chimeric antigen receptor (CAR)-T cell dysfunction, so editing exhaustion resistant CAR-T cells can enhance its anti-tumor activity and improve clinical outcomes (101, 102).”
BackgroundBrændstrup, P., Levine, B. L., & Ruella, M. (2020) · Cytotherapy · doi:10.1016/j.jcyt.2019.12.004 · Cited by 163
Chimeric antigen receptor T cell therapy for autoimmune disease
Chung, J. B., Brudno, J. N., Borie, D. C., & Kochenderfer, J. N. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01035-3 · Cited by 159
CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications
Arjomandnejad, M., Kopec, A. L., & Keeler, A. M. (2022) · Biomedicines · doi:10.3390/biomedicines10020287 · Cited by 154
“CRISPR-engineered CAR T cells, which express CAR from an endogenous TCR locus remain active for longer periods than their virus-transduced counterparts [36].”
BackgroundImmunity to CRISPR Cas9 and Cas12a therapeutics
Chew, W. L. (2017) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1408 · Cited by 150
γδ T Cells: The Ideal Tool for Cancer Immunotherapy
Yazdanifar, M., Barbarito, G., Bertaina, A., & Airoldi, I. (2020) · Cells · doi:10.3390/cells9051305 · Cited by 157
“To assure that viral gene integration does not occur at the oncogenic loci, while exploiting the potential advantage of targeted integration at a specific loci (TCRα), other editing technologies such as CRISPR/Cas9 have been designed and tested to improve engineered chimeric antigen receptor (CAR) αβ T cells function…”
BackgroundAllogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma
Bedoya, D. M., Dutoit, V., & Migliorini, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.640082 · Cited by 151
“There are different ways to avoid GVHD when designing allogeneic CAR T cells, the most widely used strategy being the generation of TCRdeficient T cells using genome editing tools such as Zinc finger nucleases (ZFN) (19–21), transcription activator-like effector nucleases (TALEN) (22–24) and CRISPR/Cas9 (25– 27).”
BackgroundInfluentialJiang, H., Li, C., Yin, P., Guo, T., Liu, L., Xia, L., Wu, Y., Zhou, F., Ai, L., Shi, W., et al. (2019) · American Journal of Hematology · doi:10.1002/ajh.25582 · Cited by 148
Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions
Bagley, S. J., & O’Rourke, D. M. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107419 · Cited by 147
Mesothelin-targeted CAR-T cell therapy for solid tumors
Klampatsa, A., Dimou, V., & Albelda, S. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2021.1843628 · Cited by 130
“There is also interest in viral-based targeted integration into the T cell receptor locus [98].”
Background3D-organoid culture supports differentiation of human CAR+ iPSCs into highly functional CAR T cells
Wang, Z., McWilliams‐Koeppen, H. P., Reza, H., Ostberg, J. R., Chen, W., Wang, X., Huynh, C., Vyas, V., Chang, W.-C., Starr, R., et al. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.02.009 · Cited by 148
Driving CARs on the uneven road of antigen heterogeneity in solid tumors
Chen, N., Li, X., Chintala, N. K., Tano, Z. E., & Adusumilli, P. S. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.03.002 · Cited by 143
Stock, S., Schmitt, M. W., & Sellner, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246223 · Cited by 146
“The CRISPR/Cas9 system combined with an adeno-associated virus (AAV) vector repair matrix was applied for the integration of the CAR encoding DNA into the T cell receptor α constant (TRAC) locus provoking an uniform expression of the CAR, an improvement of T cell potency, and an inhibition of T cell differentiation as…”
MethodEngineering-enhanced CAR T cells for improved cancer therapy
Milone, M. C., Xu, J., Chen, S., Collins, M. A., Zhou, J., Powell, D. J., & Melenhorst, J. J. (2021) · Nature Cancer · doi:10.1038/s43018-021-00241-5 · Cited by 148
Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy
Liu, Z., Shi, M., Ren, Y., Xu, H., Weng, S., Ning, W., Ge, X., Liu, L., Guo, C., Duo, M., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01738-6 · Cited by 160
“Several groups [92, 93] targeted CD19-specific CAR to the TRAC locus via CRISPR-Cas9.”
MethodNext-generation cell therapies: the emerging role of CAR-NK cells
Başar, R., Daher, M., & Rezvani, K. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020002547 · Cited by 145
Immunogenicity of CRISPR therapeutics—Critical considerations for clinical translation
Ewaisha, R., & Anderson, K. S. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1138596 · Cited by 153
“CRISPR/Cas9 has also been used for targeted knock-in of a CD19specific chimeric antigen receptor resulting in CAR T cells with uniform CAR expression and improved potency compared with the conventional CAR T cell approach (Eyquem et al., 2017; Dimitri et al., 2022).”
MethodCo-Stimulatory Receptor Signaling in CAR-T Cells
Honikel, M. M., & Olejniczak, S. H. (2022) · Biomolecules · doi:10.3390/biom12091303 · Cited by 149
“The choice of promoter in viral expression vectors, level and duration of surface expression, strength of signaling and additional structural design elements of the CAR have all been implicated in tonic signaling and effectively combating CAR-T cell exhaustion will likely require a multi-pronged approach [24,34,71,181…”
Background
Metadata
- Authors
- Eyquem, J., Mansilla-Soto, J., Giavridis, T., van der Stegen, S. J. C., Hamieh, M., Cunanan, K. M., Odak, A., Gönen, M., & Sadelain, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Sadelain, Michel
- ORCID
- Venue
- Nature
- Published
- 2017-02-22
- Volume
- 543
- Issue
- 7643
- Pages
- 113-117
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5558614
- OpenAlex
- W2589417329
- Semantic Scholar
- 47af46911569825ab86ac946a5c9cd502504aa3f
- Cited by
- 1,831
- References
- 33
- Citations by year
- 2026: 191 · 2025: 175 · 2024: 206 · 2023: 201 · 2022: 224 · 2021: 238 · 2020: 190 · 2019: 186 · 2018: 151 · 2017: 68
- FWCI
- 71.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- chimeric antigen receptor, CRISPR/Cas9 genome editing, CD19, chimeric antigen receptor T cells, T cell exhaustion, T cell differentiation, acute lymphoblastic leukemia, tumor rejection, targeted gene integration
- MeSH terms
- Gene Editing, Animals, Cell Differentiation, Disease Models, Animal, Gene Expression Regulation, Humans, Immunotherapy, Lymphocyte Activation, Male, Promoter Regions, Genetic, Receptors, Antigen, T-Cell, T-Lymphocytes, Receptors, Antigen, T-Cell, alpha-beta, Antigens, CD19, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Genetic Loci, Translational Research, Biomedical, CRISPR-Cas Systems
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