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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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KEAP1 Editing Using CRISPR/Cas9 for Therapeutic NRF2 Activation in Primary Human T Lymphocytes
Noel, S., Lee, S. A., Sadasivam, M., Hamad, A. R. A., & Rabb, H. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1700812 · Cited by 24
“Furthermore, CRISPR-based gene editing appears to produce more robust functional effects (29).”
Versatile CAR T-cells for cancer immunotherapy
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“The TRACCAR dynamic expression seems to be regulated by the TCR enhancer/promotor in response to repeated stimulation by antigen, mimicking a natural procedure of TCR regulation [37].”
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Kaushik, I., Ramachandran, S., & Srivastava, S. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.04.018 · Cited by 25
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Ackley, J. C., Ochoa, M. A., Ghoshal, D., Roy, K., Lonial, S., & Boise, L. (2021) · Cancers · doi:10.3390/cancers13194787 · Cited by 25
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Boosting CAR-T cell therapy with CRISPR technology
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CRISPR/Cas9 for the treatment of haematological diseases: a journey from bacteria to the bedside
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“As an attempt to improve CAR-T cell performance, the Sadelain group used CRISPR/Cas9 and the HDR repair pathway to generate a uniform population of CD19-specific CAR-T cells, in which the CAR transgene was precisely inserted at the TCR alpha locus (TRAC).(51) These T cells showed CAR expression under the control of th…”
MethodHematopoeitic Cell Transplantation and CAR T-Cell Therapy: Complements or Competitors?
Goldsmith, S. R., Ghobadi, A., & DiPersio, J. F. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.608916 · Cited by 25
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“CRISPR has also been used to insert CAR constructs into the TRAC locus (68).”
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“*ose αβ Tcells can be produced by using gene editing tools such as TALEN [6], ZFN, and CRISPR/CAS9 to disrupt the endogenous TCR and HLA class I (HLA-I) [7, 8], while the cδT cells can be safely applied in the allogeneic graft and cδTcells can secrete CXCL13 naturally, which regulated the migration of B cells [9].”
Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells
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Genome Editing in Engineered T Cells for Cancer Immunotherapy
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Advances of Genome Editing with CRISPR/Cas9 in Neurodegeneration: The Right Path towards Therapy
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“Along with the rapid development of gene editing technologies such as CRISPR/Cas9, the process for the manufacture of CAR-T cells is increasingly improving.(29,77) CAR design and T-cell culture techniques continue to be optimized and upgraded, and used to determine the prognosis of patients after infusion of CAR-T cel…”
MethodApplications of CRISPR-Cas in Bioengineering, Biotechnology, and Translational Research
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“223 In earlier studies, ZFNs 224–226 and TALENs 227,228 have also helped to unleash the therapeutic potential of CAR-T cell therapy by genetically editing the T cell.”
Engineering T Cells to Treat Cancer: The Convergence of Immuno-Oncology and Synthetic Biology
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“The emergence of targeted nuclease clustered regularly interspaced short palindromic repeats (CRISPR) provides a new means to specifically disrupt endogenous genes or target transgene delivery to chosen locations (19–21), potentially resulting in greater gene expression (22).”
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Interrogating immune cells and cancer with CRISPR-Cas9
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Numerical optimization of microfluidic vortex shedding for genome editing T cells with Cas9
Jarrell, J. A., Sytsma, B. J., Wilson, L. H., Pan, F. L., Lau, K. H. W. J., Kirby, G. T. S., Lievano, A. A., & Pawell, R. S. (2021) · Scientific Reports · doi:10.1038/s41598-021-91307-y · Cited by 25
Prospect of Prostate Cancer Treatment: Armed CAR-T or Combination Therapy
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“More potent CAR-T cells were produced and delayed the differentiation and depletion of effector T cells, thereby enhancing tumor immune rejection [95].”
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“While coexpression of the TCAR together with the CD3 subunits could increase TCAR-dependent signaling (42) and avoid antigen escape, the previously described TCR knockout strategies combined with TCR locus–targeted TCAR integration could support a fine-tuned TCAR signaling to avoid AICD (60).”
BackgroundA comprehensive overview of CRISPR/Cas 9 technology and application thereof in drug discovery
Khurana, A., Sayed, N., Singh, V., Khurana, I., Allawadhi, P., Rawat, P. S., Navik, U., Pasumarthi, S. K., Bharani, K. K., & Weiskirchen, R. (2022) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30329 · Cited by 22
“, where controlled gene editing was achieved using the CRISPR–Cas9 tool and the TCR gene was replaced by the CD19‐specific CAR gene into the T‐cell receptor α constant (TRAC) locus, thereby achieving a uniform expression of the CAR in human T cells.(53) The CRISPR–Cas technology has been pivotal in conferring safety t…”
MethodWho wins the combat, CAR or TCR?
Yun, K., Siegler, E. L., & Kenderian, S. S. (2023) · Leukemia · doi:10.1038/s41375-023-01976-z · Cited by 22
“Homogenous expression of CD19 CARs on TRAC-CAR-T cells was observed, while CAR-T cells generated by standard retroviral transduction (RV-CAR) showed higher mean expression of CARs with greater variations across donors [70].”
BackgroundResultInfluentialIn vivo affinity maturation of mouse B cells reprogrammed to express human antibodies
Yin, Y., Guo, Y., Jiang, Y., Quinlan, B. D., Peng, H., Crynen, G. C., He, W., Zhang, L., Ou, T., Bailey, C. C., et al. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01179-6 · Cited by 22
“Specifically, chimeric-antigen receptors expressed from an endogenous T-cell receptor alpha-chain promoter controlled tumour progression in vivo more efficiently than those expressed from an exogenous promoter 46 .”
Miao, L., Zhang, J., Xu, W., Qian, Q., Zhang, G., Yuan, Q., Lv, Y., Zhang, H., Shen, C., & Wang, W. (2024) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2024.2338984 · Cited by 22
“…are four studies related to improving the curative effect of CAR-T cells in solid tumors, such as combining CAR-T cells with PD-1 inhibitors, 24 integrating CRISPR/ Cas9 technology into CAR-T cells, 25 optimizing the CAR structure by augmenting cytokine receptor genes in the intra-cellular domain.”
BackgroundMethodCAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?
Prinzing, B. L., Gottschalk, S. M., & Krenciute, G. (2018) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2018.1451749 · Cited by 22
“In addition, expressing CARs under the control of physiological promoters, such as the TCRα promoter, has been shown to enhance CAR T-cell function [46].”
BackgroundEngineering therapeutic T cells to suppress alloimmune responses using TCRs, CARs, or BARs
Sicard, A., Levings, M. K., & Scott, D. W. (2018) · American Journal of Transplantation · doi:10.1111/ajt.14747 · Cited by 22
Targeted genome editing in acute lymphoblastic leukemia: a review
Montaño, A., Forero‐Castro, M., Hernández‐Rivas, J. M., García‐Tuñón, I., & Benito, R. (2018) · BMC Biotechnology · doi:10.1186/s12896-018-0455-9 · Cited by 23
The potential of CAR T therapy for relapsed or refractory pediatric and young adult B-cell ALL
Forsberg, M. H., Das, A., Saha, K., & Capitini, C. M. (2018) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s146309 · Cited by 22
“A recent study used CRISPR/Cas9 to direct genomic integration of a CAR construct to the T-cell receptor locus (TRAC).(65) Results demonstrated not only robust CAR expression but also enhanced T-cell potency, a reduction of inhibitory receptor expression characteristic of exhaustion (such as PD-1) and prevention of ton…”
MethodRecent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology
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CAR-Treg cell therapies and their future potential in treating ocular autoimmune conditions
Abraham, A. R., Maghsoudlou, P., Copland, D. A., Nicholson, L. B., & Dick, A. D. (2023) · Frontiers in Ophthalmology · doi:10.3389/fopht.2023.1184937 · Cited by 20
“linking the transgene to the TCR promotor region when combined with TCR knockout (76).”
BackgroundUniversal CAR 2.0 to overcome current limitations in CAR therapy
Schlegel, L. S., Werbrouck, C., Boettcher, M., & Schlegel, P. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1383894 · Cited by 21
“Since the TcR is the responsible receptor for alloreactivity in GvHD direction, the TcR-KO is the most effective strategy to silence the primary T cell function (42).”
BackgroundMethodInfluentialPetri, K., D’Ippolito, E., Künkele, A., Koehl, U., Busch, D. H., Einsele, H., & Hudecek, M. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01072-4 · Cited by 28
CAR T cell persistence in cancer
Mueller, K. P., Grenier, J. M., & Weber, E. W. (2025) · Trends in cancer · doi:10.1016/j.trecan.2025.08.014 · Cited by 22
Orthotopic T-Cell Receptor Replacement—An “Enabler” for TCR-Based Therapies
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“Proof of concept for this was first provided by the Sadelain group using adeno-associated virus (AAV)-mediated delivery of a CAR DNA template [30], and later refined through the Marson group by making this process completely non-viral and also demonstrating feasibility for TCR engineering [31].”
BackgroundMethodInfluentialThe Great War of Today: Modifications of CAR-T Cells to Effectively Combat Malignancies
Zhylko, A., Winiarska, M., & Graczyk‐Jarzynka, A. (2020) · Cancers · doi:10.3390/cancers12082030 · Cited by 21
“The phenotype of lymphocytes, the expression level of the CAR on the cell surface and even the locus of CAR DNA integration [45] can all affect CAR-T functionality.”
BackgroundMaeda, T., Nagano, S., Kashima, S., Terada, K., Agata, Y., Ichise, H., Ohtaka, M., Nakanishi, M., Fujiki, F., Sugiyama, H., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.09.011 · Cited by 21
“There are several reports that the transduction of TCRs or even CAR genes into the TCR gene locus results in better control of expression than does random integration by the virus vector because of the physiological regulation of these exogenous genes in the TCR loci.(24,25) Such TCR-locus-specific transduction in iPS…”
MethodPeraro, L., Bourne, C. M., Dacek, M. M., Akalin, E., Park, J. H., Smith, E. L., & Scheinberg, D. A. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.06.022 · Cited by 20
T cell receptor revision and immune repertoire changes in autoimmune diseases
Song, R., Jia, X., Zhao, J., Du, P., & Zhang, J. (2021) · International Reviews of Immunology · doi:10.1080/08830185.2021.1929954 · Cited by 24
“TCRs or CARs have traditionally been applied to engineering effector T cells, predominantly CD8+ cytotoxic cells, in order to treat malignant diseases, particularly hematological malignancies [137–139].”
BackgroundInfluentialKaštánková, I., Štach, M., Žižková, H., Ptáčková, P., Šmilauerová, K., Mucha, M., Šroller, V., & Otáhal, P. (2021) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2021.08.006 · Cited by 22
“It has been shown that the insertion of CAR transgene into the TCR locus disrupts the expression of endogenous TCR, which leads to improved function of CAR T cells by reducing the tonic TCR signaling.(16) However, CRISPR-Cas9 has significant offtarget effects and produces chromosomal translocations.”
Ding, M., Fei, Y., Zhu, J., Ma, J., Zhu, G., Zhen, N., Zhu, J., Mao, S., Sun, F., Wang, F., et al. (2022) · Cancer Science · doi:10.1111/cas.15374 · Cited by 20
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Self-citationJoining Forces for Cancer Treatment: From “TCR versus CAR” to “TCR and CAR”
Teppert, K., Wang, X., Anders, K., Evaristo, C., Lock, D., & Künkele, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314563 · Cited by 26
Generation and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy
Ren, J., Liao, X., Lewis, J. M., Chang, J., Qu, R., Carlson, K. R., Foss, F. M., & Girardi, M. (2024) · Nature Communications · doi:10.1038/s41467-024-44786-2 · Cited by 23
“To increase the potential persistence of allogeneic CAR-V β 2 cells in patients by reducing HVG reactivity and rejection, B2M and CIITA genes 29 were subsequently also knocked out after TRAC KO (hereafter “ triple-KO ” ) in puri fi ed pan T cells, with demonstrated down-regulation of HLA-A/B/C and HLA-DR/DP/DQ surface…”
InfluentialCRISPR/Cas9 technology: towards a new generation of improved CAR-T cells for anticancer therapies
Ureña-Bailén, G., Lamsfus‐Calle, A., Daniel-Moreno, A., Raju, J., Schlegel, P., Seitz, C. M., Atar, D., Antony, J. S., Handgretinger, R., & Mezger, M. (2019) · Briefings in Functional Genomics · doi:10.1093/bfgp/elz039 · Cited by 23
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Anti-CD19 CAR-T cells: Digging in the dark side of the golden therapy
Bouziana, S. D., & Bouzianas, D. G. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.103096 · Cited by 20
Chimeric antigen receptors: unleashing a new age of anti-cancer therapy
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“For example, clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) CRISPR/Cas9 is a targeted nuclease that can induce a double stranded break (DSB) at a defined location 15,16 .”
InfluentialSelf-citationTailoring CAR surface density and dynamics to improve CAR-T cell therapy
Hinckley-Boned, A., Barbero-Jiménez, C., Tristán‐Manzano, M., Maldonado‐Pérez, N., Hudecek, M., Justicia-Lirio, P., & Martı́n, F. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010702 · Cited by 20
“12 17–19 The transcriptional Open access control of CAR expression is better understood since it depends on the promoter and RNA structure.”
Fan, Y., Duan, Y., Chen, J., Wang, Y., Shang, K., Jiang, J., Su, L., Zhou, C., Sadelain, M., Huang, H., et al. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01450-4 · Cited by 23
“Furthermore, allogeneic NK cells from different sources were well tolerated in clinical trials without inducing GvHD 15–18 .”
InfluentialSelf-citationBiondi, A., Magnani, C. F., Tettamanti, S., Gaipa, G., & Biagi, E. (2017) · Journal of Autoimmunity · doi:10.1016/j.jaut.2017.08.003 · Cited by 20
Novel biomanufacturing platform for large-scale and high-quality human T cells production
Ou, J., Si, Y., Tang, Y., Salzer, G., Lü, Y., Kim, S., Qin, H., Zhou, L., & Liu, M. (2019) · Journal of Biological Engineering · doi:10.1186/s13036-019-0167-2 · Cited by 19
Engineering T Cells Using CRISPR/Cas9 for Cancer Therapy
Zhang, X., Cheng, C., Sun, W. C., & Wang, H. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0290-4_23 · Cited by 20
Mansourabadi, A. H., Khosroshahi, L. M., Noorbakhsh, F., & Amirzargar, A. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107669 · Cited by 21
Suematsu, M., Yagyu, S., Nagao, N., Kubota, S., Shimizu, Y., Tanaka, M., Nakazawa, Y., & Imamura, T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.770132 · Cited by 21
“Various modifications reported in CAR-T engineering to prevent early T-cell exhaustion are as follows: use of endogenic promoters for stable expression of the CAR transgene (37), use of a combination of internal ribosome entry site constructs into the CAR transgene to reduce CARtransgene expression (40), or modificati…”
MethodResultBraun, T., Pruene, A., Darguzyte, M., Stein, A. F. V., Nguyen, P., Wagner, D. L., Kath, J., Roig‐Merino, A., Heuser, M., Riehm, L. L., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1086433 · Cited by 20
“(I) Reduced frequencies of CD3+ T cells as result of the TRAC KO.”
BackgroundInfluentialWang, Y., Wang, L., Seo, N., Okumura, S., Hayashi, T., Akahori, Y., Fujiwara, H., Amaishi, Y., Okamoto, S., Mineno, J., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310873 · Cited by 24
“Antibodies and reagents; The following antibodies and regents were used for cells surface and intracellular staining; FITC-anti-human TCR Vδ2 (Clone: B6), APC-anti-human TCR Vδ2 (Clone: B6), PE-anti-human CD28 (Clone: CD28.”
BackgroundInfluentialCRISPR in Targeted Therapy and Adoptive T Cell Immunotherapy for Hepatocellular Carcinoma
Palaz, F., Özsöz, M., Zarrinpar, A., & Şahin, İ. (2024) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s456683 · Cited by 21
Lindel, F., Dodt, C., Weidner, N., Noll, M., Bergemann, F., Behrendt, R., Fischer, S., Dietrich, J., Cartellieri, M., Hamann, M. V., et al. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.10.006 · Cited by 22
“This may be an alternative as long as fully transient sgRNA provision at sufficient levels has not been implemented and CAR expression from a randomly genomic integrated additional transgene cassette is used and not a HDR-mediated replacement of endogenous TCR genes by CAR coding sequences.(60)”
Genome-edited adult stem cells: Next-generation advanced therapy medicinal products
Benabdellah, K., Sánchez-Hernández, S., Aguilar-González, A., Maldonado‐Pérez, N., Gutiérrez-Guerrero, A., Cortijo-Gutierréz, M., Ramos-Hernández, I., Tristán‐Manzano, M., Galindo‐Moreno, P., Herrera, C., et al. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.19-0338 · Cited by 21
“Eyquem et al.(90) inserted a α-CD19 CAR into the T-cell receptor A constant (TRAC) locus using Cas9 mRNA and gRNA electroporation followed by transduction with AAV6 harboring the donor DNA containing the CAR.”
MethodOverhauling CAR T Cells to Improve Efficacy, Safety and Cost
Chicaybam, L., Bonamino, M., Invitti, A. L., Rozenchan, P. B., Vieira, I. D. L., & Strauss, B. E. (2020) · Cancers · doi:10.3390/cancers12092360 · Cited by 20
“The Sadelain group [140] has used the CRISPR/Cas9 system to insert a CD19 CAR in the T cell receptor α constant (TRAC) locus.”
MethodInfluentialImmune Literacy: Reading, Writing, and Editing Adaptive Immunity
Csepregi, L., Ehling, R. A., Wagner, B., & Reddy, S. T. (2020) · iScience · doi:10.1016/j.isci.2020.101519 · Cited by 22
Industrializing engineered autologous T cells as medicines for solid tumours
Britten, C. M., Shalabi, A. M., & Hoos, A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00175-8 · Cited by 20
Mao, R., Hussein, M. S., & He, Y. (2022) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2021.32 · Cited by 21
Regulatory T Cell Therapeutics for Neuroinflammatory Disorders
Harkins, A. L., Kopec, A. L., & Keeler, A. M. (2022) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.2022045080 · Cited by 19
Yu, T., Jhita, N., Shankles, P. G., Fedanov, A., Kramer, N. B., Raikar, S. S., & Sulchek, T. (2023) · Lab on a Chip · doi:10.1039/d3lc00311f · Cited by 19
Zhang, M., Lu, X., Luo, L., Dou, J., Zhang, J., Li, G., Li, Z., & Sun, F. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02943-1 · Cited by 21
“It is widely applied across various fields, encompassing human, animal, plant, and microbial genome manipulation [19, 20].”
SEED-Selection enables high-efficiency enrichment of primary T cells edited at multiple loci
Chang, C. R., Vykunta, V. S., Lee, J. H. J., Li, L., Kochendoerfer, C., Muldoon, J. J., Wang, C. H., Mazumder, T., Sun, Y., Goodman, D. B., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-024-02531-6 · Cited by 21
“The TCR is subject to multiple pretranslational and posttranslational processes that result in functional allelic exclusion and editing at the single active TCRα allele is often sufficient to ablate TCR expression 23,27 .”
Self-citationTCR-T cell therapy for solid tumors: challenges and emerging solutions
He, W., Cui, K., Farooq, M. A., Huang, N., Zhu, S., Jiang, D., Zhang, X., Chen, J., Liu, Y., & Xu, G. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1493346 · Cited by 22
Sensitive CAR T cells redefine targetable CD70 expression in solid tumors
Hanina, S., Park, T., Lopez, M. A., Rajasekhar, V. K., Mansilla‐Soto, J., Haubner, S., Zhao, H., Kogel, F., Nataraj, S. E., Banerjee, P., et al. (2026) · Science · doi:10.1126/science.adv7378 · Cited by 19
Self-citationEl-Khazragy, N. N., Ghozy, S. A., Emad, P., Mourad, M., Razza, D., Farouk, Y. K., Mohamed, N. A., Ahmed, M. K., Youssef, T., Bahnasawy, Y. M., et al. (2020) · Immunotherapy · doi:10.2217/imt-2020-0181 · Cited by 20
Multiplexed engineering and precision gene editing in cellular immunotherapy
Biederstädt, A., Manzar, G. S., & Daher, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1063303 · Cited by 19
“For allogeneic CAR-T cells in particular, elimination of the endogenous T cell receptor (TCR) prevents the deleterious effects of alloreactivity and GvHD induction and site-directed engineering strategies now accomplish both simultaneously - deletion of the endogenous TRAC locus and CAR delivery (59, 60).”
BackgroundGermline T cell receptor exchange results in physiological T cell development and function
Rollins, M. R., Raynor, J. F., Miller, E. A., Butler, J. Z., Spartz, E. J., Lahr, W. S., You, Y., Burrack, A. L., Moriarity, B. S., Webber, B. R., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36180-1 · Cited by 18
A review of the types, functions and regulatory mechanisms of plant spines
Pei, H., Wu, Y., Wu, W., Lyu, L., & Li, W. (2024) · Plant Science · doi:10.1016/j.plantsci.2024.112010 · Cited by 19
CircRNA Regulation of T Cells in Cancer: Unraveling Potential Targets
Li, Z., Yin, S., Yang, K., Zhang, B., Wu, X., Zhang, M., & Gao, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126383 · Cited by 19
“…T cell proliferation, trafficking, and antitumor cytotoxicity Low editing efficiency leads to uncertain efficacy; safety concerns due to potential genomic damage [35] Among these strategies, CAR-T cell and TCR-T cell immunotherapies have garnered significant clinical attention in recent years.”
BackgroundBuilding a novel TRUCK by harnessing the endogenous IFN-gamma promoter for cytokine expression
Ma, L., Zhang, K., Xu, J., Wang, J., Jiang, T., Du, X., Zhang, J., Huang, J., Ren, F., Liu, D., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.06.017 · Cited by 19
“21 To reduce costs and streamline the manufacturing process, we explored delivering two repair templates using a single AAV vector.”
iPSC Technology Revolutionizes CAR-T Cell Therapy for Cancer Treatment
Zong, J., & Li, Y.-R. (2025) · Bioengineering · doi:10.3390/bioengineering12010060 · Cited by 20
“For instance, when TCR TRAC is knocked out, host immune recognition is abrogated, forestalling subsequent reactions, notably GvHD initiation [34–36].”
Jakobczyk, H., Sciortino, F., Chevance, S., Gauffre, F., & Troadec, M. (2017) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2017.07.075 · Cited by 19
“ALL!patients.!J.!”
BackgroundInfluentialBlossom of CRISPR technologies and applications in disease treatment
Liu, H., Wang, L., & Luo, Y. (2018) · Synthetic and Systems Biotechnology · doi:10.1016/j.synbio.2018.10.003 · Cited by 19
“In another case, the CAR was integrated into the TRC locus precisely under the control of endogenous regulatory elements, which can reduce tonic signaling, avert accelerated T-cell differentiation and exhaustion, and also increase the therapeutic potency of engineered T cells [179].”
Synergistic combination of oncolytic virotherapy with CAR T-cell therapy
Ajina, A., & Maher, J. F. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.06.015 · Cited by 20
Replacing CAR-T cell resistance with persistence by changing a single residue
Hsieh, E. M., Scherer, L. D., & Rouce, R. H. (2020) · Journal of Clinical Investigation · doi:10.1172/jci136872 · Cited by 18
Natural killer cell engineering – a new hope for cancer immunotherapy
Lin, C., Gobius, I., & Souza-Fonseca-Guimarães, F. (2020) · Seminars in Hematology · doi:10.1053/j.seminhematol.2020.10.002 · Cited by 19
How Can We Engineer CAR T Cells to Overcome Resistance?
Glover, M., Avraamides, S., & Maher, J. F. (2021) · Biologics · doi:10.2147/btt.s252568 · Cited by 19
“CAR T cells with a less differentiated phenotype and reduced exhaustion.(33) In contrast to CD28 variants, 41BB-containing CAR T cells demonstrate slower anti-tumour kinetics, yet improved persistence.”
BackgroundMaganti, H. B., Kirkham, A. M., Bailey, A. J.-M., Shorr, R., Kekre, N. K., Pineault, N., & Allan, D. (2022) · Cytotherapy · doi:10.1016/j.jcyt.2021.10.010 · Cited by 20
New developments in immunotherapy for pediatric solid tumors
Schultz, L. M., Majzner, R. G., Davis, K. L., & Mackall, C. L. (2017) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000564 · Cited by 19
Application of CAR T cells for the treatment of solid tumors
Khan, J. F., Khan, A. S., & Brentjens, R. J. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.07.004 · Cited by 19
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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