The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells
Open accessAbstract
Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies 1-3. In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells 4,5. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.
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In the citing paper
“However, the composition of autologous starting material from cancer patients is highly variable, influenced by patient age and defects due to underlying disease or pre-treatment with lymphotoxic agents (35-38).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [38]
Experimental — accuracy not yet measuredIn the citing paper
“T cells with a lentiviral integration disrupting TET2 showed strong preferential expansion at the peak of a patient’s response and likely contributed to this complete response to CAR T cell therapy.”
From Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function (2018) · cites this paper as Fraietta et al., 2018
In the citing paper
“The potential power of human primary T cell loss-of-function screens was recently demonstrated in a patient who received CAR T cell therapy for chronic lymphocytic leukemia (CLL) (Fraietta et al., 2018).”
From Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function (2018) · cites this paper as Fraietta et al., 2018
In the citing paper
“There is also a report of an exceptional response in a patient with CLL treated by infusion of chimeric antigen receptor (CAR) T-cells in which the CAR construct disrupted one copy of TET2, while the other copy had been previously mutated somatically 96.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [96]
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Citations
Cites
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013) · Nature Methods · doi:10.1038/nmeth.2688 · Cited by 6,422
Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L. M., Liu, D. R., Aravind, L., et al. (2009) · Science · doi:10.1126/science.1170116 · Cited by 5,836
Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia
Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., Bader, P., Verneris, M. R., Stefanski, H. E., Myers, G. D., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1709866 · Cited by 5,735
Self-citationChimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407222 · Cited by 5,413
Self-citationSummaries of Affymetrix GeneChip probe level data
Irizarry, R. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng015 · Cited by 4,837
Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A., & June, C. H. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103849 · Cited by 3,565
Self-citationTet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., He, C., & Zhang, Y. (2011) · Science · doi:10.1126/science.1210597 · Cited by 3,451
Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA
He, Y., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., et al. (2011) · Science · doi:10.1126/science.1210944 · Cited by 2,776
Self-citationThe Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain
Kriaucionis, S., & Heintz, N. (2009) · Science · doi:10.1126/science.1169786 · Cited by 2,700
Ito, S., D’Alessio, A. C., Taranova, O., Hong, K., Sowers, L. C., & Zhang, Y. (2010) · Nature · doi:10.1038/nature09303 · Cited by 2,628
Cited by
Sorted by citations
Items 201–300 of 862
Mechanisms of T cell exhaustion guiding next-generation immunotherapy
Zebley, C. C., & Youngblood, B. (2022) · Trends in Cancer · doi:10.1016/j.trecan.2022.04.004 · Cited by 65
Ahn, T., Bae, E., & Seo, H. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.04.004 · Cited by 71
“81 Considering several aspects of the role of TET2 in T cell differentiation and the feasibility of using TET2 as a gene-editing target for adoptive cell therapy are crucial.”
InfluentialT cell malignancies after CAR T cell therapy in the DESCAR-T registry
Duléry, R., Guiraud, V., Choquet, S., Thiéblemont, C., Bachy, E., Barète, S., Todesco, È., Arnulf, B., Boissel, N., Baruchel, A., et al. (2025) · Nature Medicine · doi:10.1038/s41591-024-03458-w · Cited by 67
State-of-the-art for CAR T-cell therapy for chronic lymphocytic leukemia in 2019
Lemal, R., & Tournilhac, O. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0686-x · Cited by 67
Chaudhury, A., Zhu, X., Chu, L., Goliaei, A., June, C. H., Kearns, J. D., & Stein, A. M. (2020) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.1691 · Cited by 63
Self-citationNon-viral transfection technologies for next-generation therapeutic T cell engineering
Raes, L., Smedt, S. C. D., Raemdonck, K., & Braeckmans, K. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107760 · Cited by 67
García-Prieto, C. A., Villanueva, L., Bueno-Costa, A., Dávalos, V., González‐Navarro, E. A., Juan, M., Urbano-Ispizúa, Á., Delgado, J., Ortiz‐Maldonado, V., Bufalo, F. D., et al. (2021) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djab194 · Cited by 64
“Thus, biomarkers of the efficacy of adoptive cell therapy, similar to those cited here (5-9,37), and the DNA methylation markers discovered in our study almost certainly await discovery.”
BackgroundLi, N., Quan, A., Li, D., Pan, J., Ren, H., Hoeltzel, G. D., de Val, N., Ashworth, D., Ni, W., Zhou, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37616-4 · Cited by 65
Lei, X., Ou, Z., Yang, Z., Zhong, J., Zhu, Y., Tian, J., Wu, J., Deng, H., Lin, X., Yu, P., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2487 · Cited by 64
“CAR T cells increased granzyme B and perforin levels as well as their cytotoxic activity; these results are in agreement the information in the literature (11).”
BackgroundResultInfluentialFrequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias
Olson, T. L., Cheon, H., Xing, J. C., Olson, K. C., Paila, U., Hamele, C. E., Neelamraju, Y., Shemo, B. C., Schmachtenberg, M. W., Sundararaman, S. K., et al. (2021) · Blood · doi:10.1182/blood.2020005831 · Cited by 63
Advances in Developing CAR T-Cell Therapy for HIV Cure
Qi, J., Ding, C., Jiang, X. L., & Gao, Y. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00361 · Cited by 72
“knocked down methylcytosine dioxygenase TET2 gene to improve the expansion and efficacy of CAR T cells and observed that, in one subject, 94% of CAR T cells likely originated from a single colony in which the TET2 gene was disrupted by the integrated CAR gene (117).”
BackgroundTime to evolve: predicting engineered T cell-associated toxicity with next-generation models
Donnadieu, E., Luu, M., Alb, M., Anliker, B., Arcangeli, S., Bonini, C., Angelis, B. D., Choudhary, R., Espie, D., Galy, A. H. M., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003486 · Cited by 66
Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia
Lundgren, S., Keränen, M. A. I., Kankainen, M., Huuhtanen, J., Walldin, G., Kerr, C. M., Clemente, M. J., Ebeling, F. T., Rajala, H. L. M., Brück, O. E., et al. (2021) · Leukemia · doi:10.1038/s41375-021-01231-3 · Cited by 63
“in response to stimulus and killed tumor cells more efficiently [65].”
Teipel, R., Kroschinsky, F., Krämer, M., Kretschmann, T., Egger‐Heidrich, K., Kruger, T. E., Ruhnke, L., Herold, S., Stasik, S., Sockel, K., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2021005747 · Cited by 68
Engineering chimeric antigen receptor T cells for solid tumour therapy
Liu, L., Qu, Y., Cheng, L., Yoon, C. W., He, P., Monther, A., Guo, T., Chittle, S. J., & Wang, Y. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.1141 · Cited by 61
Self-citationGlutarate regulates T cell metabolism and anti-tumour immunity
Minogue, E., Cunha, P. P., Wadsworth, B. J., Grice, G. L., Sah‐Teli, S. K., Hughes, R. J. F., Bargiela, D., Quaranta, A., Zurita, J., Antrobus, R., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00855-2 · Cited by 60
Engineering strategies to safely drive CAR T-cells into the future
Rossi, M., & Breman, E. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1411393 · Cited by 68
Fueling CARs: metabolic strategies to enhance CAR T-cell therapy
der Vreken, A. V., Vanderkerken, K., Bruyne, E. D., Veirman, K. D., Breckpot, K., & Menu, E. (2024) · Experimental Hematology and Oncology · doi:10.1186/s40164-024-00535-1 · Cited by 61
Targeted T cell receptor gene editing provides predictable T cell product function for immunotherapy
Müller, T. R., Jarosch, S., Hammel, M., Leube, J., Grassmann, S. A., Bernard, B. E., Effenberger, M. J. P., Andrä, I., Chaudhry, M. Z., Kaeuferle, T., et al. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100374 · Cited by 60
“15– 17 However, there are also reports of insertional mutations upon conventional editing in stem cells 58 and CAR-T cells 59 highlighting a certain need for caution.”
Engineered natural killer cells for cancer therapy
Biederstädt, A., & Rezvani, K. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.09.013 · Cited by 62
Adoptive T-cell therapy for HBV-associated HCC and HBV infection
Tan, A. T., & Schreiber, S. (2020) · Antiviral Research · doi:10.1016/j.antiviral.2020.104748 · Cited by 58
Rausch, L., & Kallies, A. (2025) · Annual Review of Immunology · doi:10.1146/annurev-immunol-082223-044122 · Cited by 66
Systematic discovery of CRISPR-boosted CAR T cell immunotherapies
Datlinger, P., Pankevich, E. V., Arnold, C. D., Pranckevicius, N., Lin, J., Romanovskaia, D., Schaefer, M., Piras, F., Orts, A.-C., Nemc, A., et al. (2025) · Nature · doi:10.1038/s41586-025-09507-9 · Cited by 63
Emerging immunotherapies for malignant glioma: from immunogenomics to cell therapy
Dunn, G. P., Cloughesy, T. F., Maus, M. V., Prins, R. M., Reardon, D. A., & Sonabend, A. M. (2020) · Neuro-Oncology · doi:10.1093/neuonc/noaa154 · Cited by 56
Shao, L., Shi, R., Zhao, Y., Liu, H., Lu, A., Ma, J., Cai, Y., Fuksenko, T., Pelayo, A., Shah, N. N., et al. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03729-5 · Cited by 56
“CAR T-cells with viral vector integration events in the exons of TET2 and CBL have resulted in clonal expansion and complete disease remission [6, 7].”
BackgroundSelf-citationLee, J., Sheen, J. H., Lim, O., Lee, Y. J., Ryu, J., Shin, D., Kim, Y. Y., & Kim, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-74772-9 · Cited by 54
Aggressive Lymphoma after CD19 CAR T-Cell Therapy
Kobbe, G., Brüggemann, M., Baermann, B., Wiegand, L., Trautmann, H., Yousefian, S., Libertini, S., Menssen, H. D., Maier, H. J., Ulrich, P. C., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2402730 · Cited by 60
Transfection with Nanostructure Electro‐Injection is Minimally Perturbative
Tay, A. K. P., & Melosh, N. A. (2019) · Advanced Therapeutics · doi:10.1002/adtp.201900133 · Cited by 56
Greenbaum, U., Mahadeo, K. M., Kebriaei, P., Shpall, E. J., & Saini, N. Y. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01594 · Cited by 56
Massively parallel knock-in engineering of human T cells
Dai, X., Park, J. J.-Y., Du, Y., Na, Z., Lam, S. Z., Chow, R. D.-W., Renauer, P. A., Gu, J., Shan, X., Chu, Z., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01639-x · Cited by 56
Steffin, D., Muhsen, I. N., Hill, L. C., Ramos, C. A., Ahmed, N. M., Hegde, M. G., Wang, T., Wu, M.-F., Gottschalk, S. M., Whittle, S. B., et al. (2022) · Blood · doi:10.1182/blood.2022015728 · Cited by 53
All systems go: converging synthetic biology and combinatorial treatment for CAR-T cell therapy
Lanitis, E., Coukos, G., & Irving, M. B. (2020) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2020.01.009 · Cited by 52
DNA Methylation in T-Cell Development and Differentiation
Correa, L. O., Jordan, M. S., & Carty, S. A. (2020) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.2020033728 · Cited by 52
Self-citationIntegration of ζ-deficient CARs into the CD3 ζ gene conveys potent cytotoxicity in T and NK cells
Kath, J., Franke, C., Drosdek, V., Du, W., Glaser, V., Fuster‐García, C., Stein, M., Zittel, T., Schulenberg, S., Porter, C. E., et al. (2024) · Blood · doi:10.1182/blood.2023020973 · Cited by 52
CD5 deletion enhances the antitumor activity of adoptive T cell therapies
Patel, R. P., Ghilardi, G., Zhang, Y., Chiang, Y., Xie, W., Guruprasad, P., Kim, K. H., Chun, I., Angelos, M. G., Pajarillo, R., et al. (2024) · Science Immunology · doi:10.1126/sciimmunol.adn6509 · Cited by 55
“Numerous other KOs have been explored in preclinical models as strategies to enhance CAR T function, including RASA2 ( 61 ), PTPN2 ( 62 ), TET2 ( 63 ), CTLA4 ( 59 ), and several others.”
BackgroundA CAR enhancer increases the activity and persistence of CAR T cells
Rakhshandehroo, T., Mantri, S. R., Moravej, S. H., Louis, B. B. V., Farid, A. S., Munaretto, L., Regan, K., Khan, R. M. M., Wolff, A. N., Farkash, Z., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02339-4 · Cited by 55
Succinate preserves CD8+ T cell fitness to augment antitumor immunity
Ma, K., Cheng, H., Wang, L., Xiao, H., Liu, F., Yang, Y. T., Xiao, Z., Tang, K., Li, S., Wang, G., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.07.017 · Cited by 57
Self-citationGoing to extremes: determinants of extraordinary response and survival in patients with cancer
Saner, F. A. M., Herschtal, A., Nelson, B. H., DeFazio, A., Goode, E. L., Ramus, S. J., Pandey, A., Beach, J. A., Fereday, S., Berchuck, A., et al. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0145-5 · Cited by 51
Ma, F., Ho, J., Du, H., Fan, X., Wu, X., Wang, Q., Wang, L., Liu, Y., Ba, M., Wang, Y., et al. (2019) · Hematological Oncology · doi:10.1002/hon.2672 · Cited by 52
Self-citationNK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development
Dezfouli, A. B., Yazdi, M., Pockley, A. G., Khosravi, M., Kobold, S., Wagner, E., & Multhoff, G. (2021) · Cells · doi:10.3390/cells10123390 · Cited by 53
Yang, S., Xu, J., Dai, Y., Jin, S., Sun, Y., Li, J., Liu, C.-L., Ma, X., Zhu, C. H., Chen, L., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44648-3 · Cited by 54
“…inthe anti-CD19 CAR-T therapy (referred to as the CD19 CAR-Tcase,hereafter),inwhich,theCAR-Tinfusedforthesecondtimebore TET2 sequence abnormalities on both alleles, enabling clonal proliferation of CD8 + central memory CAR-T, and rapidly achieving tumor clearanceaccompaniedbyhigh-gradeCRS 44 .”
Self-citationAzeez, S. S., Yashooa, R. K., Smail, S., Salihi, A., Ali, A. S., Mamand, S., & Janson, C. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02386-8 · Cited by 56
“Furthermore, FOXO1 over-expression or TET2 knockout can further enhance CAR-T durability [197, 198].”
Wang, X., Luo, X., Xiao, R., Liu, X., Zhou, F., Jiang, D., Bai, J., Cui, M., You, L., & Yupei, Z. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02334-4 · Cited by 59
Self-citationEpigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects
Gambacorta, V., Gnani, D., Vago, L., & Micco, R. D. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00207 · Cited by 49
Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes
Lee, M., Li, J., Li, J., Fang, S., Zhang, J., Vo, A. T. T., Han, W., Zeng, H., Isgandarova, S., Martinez-Moczygemba, M., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3213 · Cited by 47
“infiltrating myeloid cells (13,14) improves immunotherapy efficiency, suggesting the beneficial effects 75 of TET2 inactivation during anti-tumor immunotherapy.”
BackgroundSingle-cell sorting based on secreted products for functionally defined cell therapies
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Golikova, E., Alshevskaya, A., Alrhmoun, S., Sivitskaya, N. A., & Sennikov, S. V. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05703-9 · Cited by 50
“Insertion disrupted the gene’s structure and function, leading to the expansion of a therapeutically effective and significant cell clone [119].”
Evolution of chimeric antigen receptor (CAR) T cell therapy: current status and future perspectives
Lee, Y.-H., & Kim, C. H. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-019-01136-x · Cited by 50
TET2 promotes anti‐tumor immunity by governing G‐MDSCs and CD8+ T‐cell numbers
Li, S., Feng, J., Wu, F., Cai, J., Zhang, X., Wang, H., Fetahu, I. S., Iwanicki, I. J., Ma, D., Hu, T., et al. (2020) · EMBO Reports · doi:10.15252/embr.201949425 · Cited by 46
“A report on CAR-T therapy noted that TET2-deficient CAR-T cells unexpectedly gain growth advantages without alterations in their tumor cell-killing function (Fraietta et al , 2018).”
Janelle, V., & Delisle, J. (2021) · Cancers · doi:10.3390/cancers13040598 · Cited by 52
Metanat, Y., Viktor, P., Amajd, A., Kaur, I., Hamed, A. M., Al-Abadi, N. K. A., Alwan, N. H., Chaitanya, M., Natrayan, L., Ghildiyal, P., et al. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122683 · Cited by 49
Infusion and delivery strategies to maximize the efficacy of CAR-T cell immunotherapy for cancers
Gu, X., Zhang, Y., Zhou, W., Wang, F., Yan, F., Gao, H., & Wang, W. (2024) · Experimental Hematology and Oncology · doi:10.1186/s40164-024-00542-2 · Cited by 49
“Next, we focus on summarizing the clinical infusion schemes of CAR-T cells for hematological tumors [30–34].”
MethodThe epigenetic hallmarks of immune cells in cancer
Yu, J. H., Xiao, C., Fan, T. T., Deng, Z., Wang, D., Cai, W., Li, J., Liao, T., Li, C., & He, J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02255-4 · Cited by 52
“Tet2 -deleted CAR-T cells demonstrate enhanced clinical efficacy in treating chronic lymphocytic leukemia and prostate cancer, suggesting the potential of TET2 inhibitors in sensitizing CAR-T therapy [369, 370].”
Wang, W., Fasolino, M., Cattau, B., Goldman, N., Kong, W., Frederick, M. A., McCright, S. J., Kiani, K., Fraietta, J. A., & Vahedi, G. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1919259117 · Cited by 47
“We applied EpiVIA to the ATAC-seqofHEK293Tcelllineswithknownintegrationsitesandtheeffective CAR-TclonalcellsfromarecentlyreportedCLLpatient(16).”
InfluentialSelf-citationClonal hematopoiesis and its emerging effects on cellular therapies
Bonin, M. V., Jambor, H. K., Teipel, R., Stölzel, F., Thiede, C., Damm, F., Kroschinsky, F., Schetelig, J., Chavakis, T., & Bornhäuser, M. (2021) · Leukemia · doi:10.1038/s41375-021-01337-8 · Cited by 50
“Compound heterozygous TET2mutated CAR T cells were less prone to senescence and showed prolonged activation capacity after repetitive CAR-specific stimulation [97].”
BackgroundXu, Y., Li, P., Liu, Y., Xin, D., Lei, W., Liang, A., Han, W., & Qian, W. (2022) · 癌症：英文版 · doi:10.1002/cac2.12313 · Cited by 47
Wang, J., Zhang, X., Zhou, Z., Liu, Y., Li, Y., Jia, L., Yang, J., Li, J., Yu, H., Li, W., et al. (2022) · American Journal of Hematology · doi:10.1002/ajh.26586 · Cited by 45
Relapse after CAR-T cell therapy in B-cell malignancies: challenges and future approaches
Gu, T., Zhu, M., Huang, H., & Hu, Y. (2022) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2200256 · Cited by 45
“Sequencing results of CAR-T cells at the stage of peak response showed that the insertion of a CAR gene into the ten-eleven translocation 2 (TET2) gene induced unfunctional methylcytosine dioxygen‐ ase and inhibition of exhaustion (Fraietta et al., 2018b).”
BackgroundMethodT-cell lymphoma secondary to checkpoint inhibitor therapy
Anand, K., Ensor, J., Pingali, S. R., Hwu, P., Duvic, M. A., Chiang, S. B., Miranda, R. N., Zu, Y., & Iyer, S. P. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000104 · Cited by 46
Reversing T-cell exhaustion in immunotherapy: a review on current approaches and limitations
Tabana, Y., Moon, T. C., Siraki, A. G., Elahi, S., & Barakat, K. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1937123 · Cited by 47
“other lymphoid and non-lymphoid cells [95,96].”
BackgroundCAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice
Li, N., Torres, M. B., Spetz, M. R., Wang, R., Peng, L., Tian, M., Dower, C. M., Nguyen, R., Sun, M., Tai, C., et al. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100297 · Cited by 47
CHIP‐associated mutant ASXL1 in blood cells promotes solid tumor progression
Liu, X., Sato, N., Shimosato, Y., Wang, T., Denda, T., Chang, Y., Yabushita, T., Fujino, T., Asada, S., Tanaka, Y., et al. (2022) · Cancer Science · doi:10.1111/cas.15294 · Cited by 42
Self-citationCell metabolism-based optimization strategy of CAR-T cell function in cancer therapy
Li, W., Pan, X., Chen, L., Cui, H., Mo, S., Pan, Y., Shen, Y., Shi, M., Wu, J., Luo, F., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1186383 · Cited by 49
Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies
Dabiri, H., Kozani, P. S., Habibi‐Anbouhi, M., Godarzee, M. M., Haddadi, M. H., Basiri, M., Ziaei, V., Sadeghizadeh, M., & Saffar, E. H. (2023) · Biomarker Research · doi:10.1186/s40364-023-00509-1 · Cited by 45
“TET2 Disruption by CAR transgene T cells TET2 dysfunction results in the production of effective CAR T cells, which have the characteristics of short-lived memory cells that can mediate effector responses, as well as long-lived, persistent memory cells [43]”
BackgroundInfluentialSynthetic manipulation of the cancer-immunity cycle: CAR-T cell therapy
Singh, N., & Maus, M. V. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.010 · Cited by 44
In vivo site-specific engineering to reprogram T cells
Nyberg, W. A., Bernard, P.-L., Ngo, W., Wang, C. H., Ark, J., Rothrock, A., Borgo, G. M., Kimmerly, G. R., Jung, J. H., Allain, V., et al. (2026) · Nature · doi:10.1038/s41586-026-10235-x · Cited by 55
“Lentiviral vector envelopes can be engineered to provide improved specificity towards T cells 12,16,22–24 , but any transduced non-T cells would also express the CAR unless a lineage-specific promoter is used and, while rare, are at potential risk of insertional mutagenesis 25,26 .”
Bertaina, A., & Roncarolo, M. G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01342 · Cited by 45
“Retroviral or lentiviral engineered T cells also potentially carry the risk of transformation from insertional mutagenesis (92).”
BackgroundRetrieval of vector integration sites from cell-free DNA
Cesana, D., Calabria, A., Rudilosso, L., Gallina, P., Benedicenti, F., Spinozzi, G., Schiroli, G., Magnani, A., Acquati, S., Fumagalli, F., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01389-4 · Cited by 44
Self-citationIL-12 Signaling Promotes TET2-Mediated DNA Demethylation During CD8 T Cell Effector Differentiation
Zebley, C. C., Abdelsamed, H. A., Ghoneim, H. E., Alli, S., Brown, C., Haydar, D., Tian, M., Harris, T. L., McGargill, M. A., Krenciute, G., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2021.109796 · Cited by 45
“Our findings provide additional insight into recent reports showing improved clinical efficacy coupled to CAR T cells that had a mutation in TET2 and ultimately enriched for survival of TET2 KO CAR T cells with a central memory phenotype (Fraietta et al., 2018).”
ResultT cell-based cancer immunotherapy: opportunities and challenges
Ma, K., Xu, Y., Cheng, H., Tang, K., Ma, J., & Huang, B. (2025) · 中国科学通报：英文版 · doi:10.1016/j.scib.2025.03.054 · Cited by 47
Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque
Espinoza, D. A., Fan, X., Yang, D., Cordes, S., Truitt, L. L., Calvo, K. R., Yabe, I. M., Demirci, S., Hope, K. J., Hong, S. G., et al. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.04.003 · Cited by 41
“T cell clone in a patient was linked to an LV insertion inactivating the epigenetic regulator TET2.”
BackgroundExploiting Single-Cell Tools in Gene and Cell Therapy
Bode, D., Cull, A. H., Rubio-Lara, J. A., & Kent, D. G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.702636 · Cited by 44
The Fate(s) of CAR T-Cell Therapy: Navigating the Risks of CAR+ T-Cell Malignancy
Abou‐El‐Enein, M. (2024) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-23-0272 · Cited by 45
Heyman, B. M., & Yang, Y. (2019) · Cancers · doi:10.3390/cancers11020191 · Cited by 43
“Further analysis of the TET2 disrupted CAR T cells revealed that they exhibited altered differentiation, skewed towards a TCM, with enhanced cytotoxic and cytolytic function, potentially explaining the clinical response in the patient [131].”
BackgroundImai, N., Tawara, I., Yamane, M., Muraoka, D., Shiku, H., & Ikeda, H. (2020) · Cancer Science · doi:10.1111/cas.14420 · Cited by 46
Role of ten‐eleven translocation proteins and 5‐hydroxymethylcytosine in hepatocellular carcinoma
Wang, P., Yan, Y., Yu, W., & Zhang, H. (2019) · Cell Proliferation · doi:10.1111/cpr.12626 · Cited by 41
Epigenetic regulation of T cell adaptive immunity
Frias, A. B., Boi, S. K., Lan, X., & Youngblood, B. (2021) · Immunological Reviews · doi:10.1111/imr.12943 · Cited by 44
RNA Therapeutics for Improving CAR T-cell Safety and Efficacy
Schaible, P., Bethge, W. A., Lengerke, C., & Haraszti, R. Á. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-2155 · Cited by 43
Böhm, S., Wustrau, K., Schmid, J. P., Prader, S., Ahlmann, M., Yacobovich, J., Beier, R., Speckmann, C., Behnisch, W., Ifversen, M., et al. (2023) · Blood · doi:10.1182/blood.2023022281 · Cited by 41
Self-citationSMAD7 expression in CAR-T cells improves persistence and safety for solid tumors
Liang, S., Zheng, R., Zuo, B., Li, J., Wang, Y., Han, Y., Dong, H., Zhao, X., Zhang, Y., Wang, P., et al. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01120-y · Cited by 42
Self-citationChimeric Antigen Receptor Cell Therapy: Overcoming Obstacles to Battle Cancer
Petty, A. J., Heyman, B. M., & Yang, Y. (2020) · Cancers · doi:10.3390/cancers12040842 · Cited by 40
“reported a case of CAR-T integration into the Tet methylcytosine dioxygenase (TET2) locus, leading to impressive potency of the particular clone in a CLL patient [75].”
BackgroundCRISPR screen in mechanism and target discovery for cancer immunotherapy
Liu, D., Zhao, X., Tang, A., Xu, X., Liu, S., Zha, L., Ma, W., Zheng, J., & Shi, M. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188378 · Cited by 44
Foskolou, I. P., Barbieri, L., Vernet, A., Bargiela, D., Cunha, P. P., Veliça, P., Suh, E., Pietsch, S., Matulevičiūtė, R., Rundqvist, H., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020002309 · Cited by 40
“A known S-2HG target is the ten-eleven translocation 2 (TET2) demethylase, the inhibition of which has been correlated with the production of central memory CAR-T cells and complete tumor remission in a patient.(17)”
BackgroundEpigenetics and CD8+ T cell memory*
Montacchiesi, G., & Pace, L. (2021) · Immunological Reviews · doi:10.1111/imr.13057 · Cited by 43
Clonal hematopoiesis: Molecular and clinical implications
Kusne, Y. N., Xie, Z., & Patnaik, M. M. (2022) · Leukemia Research · doi:10.1016/j.leukres.2022.106787 · Cited by 43
Lymphoid clonal hematopoiesis: implications for malignancy, immunity, and treatment
von Beck, K., von Beck, T. A., Ferrell, P. B., Bick, A. G., & Kishtagari, A. (2023) · Blood Cancer Journal · doi:10.1038/s41408-022-00773-8 · Cited by 45
“This single CAR T-cell happened to have only a single hypomorphic TET2 allele, as the lentivirus carrying the CAR transgene disrupted the other TET2 allele upon gene insertion [95].”
BackgroundClinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients
Panagiota, V., Kerschbaum, J. F., Penack, O., Stein, C. M., Arends, C. M., Koenecke, C., Strzelecka, P. M., Kloos, A., Wiegand, L., Lasch, A., et al. (2023) · HemaSphere · doi:10.1097/hs9.0000000000000957 · Cited by 44
“…experimental knockdown of TET2 provided evidence for increased efficacy of CAR T-cells harboring TET2 alterations in a patient with CLL. 19 To gain further insights into the importance of CH in the context of CAR T-cell therapies, we investigated CH in a cohort of 110 r/r B-NHL or acute…”
BackgroundProgress and pitfalls of gene editing technology in CAR-T cell therapy: a state-of-the-art review
Moradi, V., Khodabandehloo, E., Alidadi, M., Omidkhoda, A., & Ahmadbeigi, N. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1388475 · Cited by 42
Ottaviano, G., & Qasim, W. (2025) · Leukemia · doi:10.1038/s41375-025-02585-8 · Cited by 45
“For example, one patient with chronic lymphoid leukaemia (CLL) who had received two infusions of CTL019 CAR-T cells experienced a delayed CAR T cell expansion that was found to be clonal [55].”
Gargett, T., Truong, N. T., Ebert, L. M., Yu, W., & Brown, M. P. (2019) · Cytotherapy · doi:10.1016/j.jcyt.2019.03.003 · Cited by 39
Ringquist, R., Ghoshal, D., Jain, R., & Roy, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114003 · Cited by 39
How metabolism bridles cytotoxic CD8+ T cells through epigenetic modifications
Acker, H. H. V., Ma, S., Scolaro, T., Kaech, S. M., & Mazzone, M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.03.006 · Cited by 39
“One case described a chronic lymphocytic leukemia (CLL) patient who achieved a complete response, with no evidence of CLL in his bone marrow, owing to the expansion of a single T cell clone with a CAR lentiviral integration site in the TET2 gene [107].”
BackgroundBraun, T., Rade, M., Merz, M., Klepzig, H., Große, F., Fandrei, D., Pham, N.-N., Kreuz, M., Kuhn, C. K., Kuschel, F., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03499-9 · Cited by 47
“In line, biallelic TET2 disruption, by integration of the CAR transgene into the TET2 gene, accompanied by a hypomorphic mutation of the second allele, enhanced the therapeutic efficacy of CD19-targeted T cells 37 .”
Chimeric antigen receptor-modified T cell therapy in chronic lymphocytic leukemia
Zou, Y., Xu, W., & Li, J. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0676-3 · Cited by 41
TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation
Shen, Y., Liu, L., Wang, M., Xu, B., Lyu, R., Shi, Y. G., & Tan, L. (2021) · Cancers · doi:10.3390/cancers13092207 · Cited by 39
Current State of CAR T-Cell Therapy in Chronic Lymphocytic Leukemia
Mančíková, V., & Šmída, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115536 · Cited by 39
“The locations of CAR vector integration acceptor sites in the T-cell genome seem to play a role in the clinical outcome [59,60].”
BackgroundZhang, Y., Li, J., Lou, X., Chen, X., Yu, Z., Kang, L., Chen, J., Zhou, J., Zong, X., YANG, Z. K., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.664421 · Cited by 37
“2 months after CAR T cells administration in response to antigen reappearance due to tumor relapse (22).”
BackgroundDimitri, A. J., Baxter, A. E., Chen, G. M., Hopkins, C. R., Rouin, G. T., Huang, H., Kong, W., Holliday, C., Wiebking, V., Bartoszek, R. L., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp9371 · Cited by 42
“TET2 loss correlates with clinical response to CAR T cell therapy ( 10 ), and its deletion promotes acquisition of a memory CD8 + T cell fate in the setting of acute infection ( 14 ).”
InfluentialSelf-citationNon-viral siRNA delivery to T cells: Challenges and opportunities in cancer immunotherapy
Hoeck, J. V., Braeckmans, K., Smedt, S. C. D., & Raemdonck, K. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121510 · Cited by 37
Zhou, Z., Xu, J., Liu, S., Lv, Y., Zhang, R., Zhou, X., Zhang, Y., Weng, S., Xu, H. W., Ba, Y., et al. (2024) · Biomarker Research · doi:10.1186/s40364-024-00630-9 · Cited by 37
“Targeting TETs, therefore, presents an appealing option to judiciously stop immune suppression in TIME [57].”
BackgroundSelf-citation
Metadata
- Authors
- Fraietta, J. A., Nobles, C. L., Sammons, M. A., Lundh, S., Carty, S. A., Reich, T. J., Cogdill, A. P., Morrissette, J. J. D., DeNizio, J. E., Reddy, S., Hwang, Y., Gohil, M., Kulikovskaya, I., Nazimuddin, F., Gupta, M., Chen, F., Everett, J. K., Alexander, K. A., Lin-Shiao, E., Gee, M. H., Liu, X., Young, R. M., Ambrose, D., Wang, Y., Xu, J., Jordan, M. S., Marcucci, K. T., Levine, B. L., Garcia, K. C., Zhao, Y., Kalos, M., Porter, D. L., Kohli, R. M., Lacey, S. F., Berger, S. L., Bushman, F. D., June, C. H., & Melenhorst, J. J.
- Affiliations
- Abramson Cancer Center (US)
- University of Pennsylvania (US)
- State University of New York (US)
- University of Michigan (US)
- Stanford Medicine (US)
- Parker Institute for Cancer Immunotherapy (US)
- Corresponding author
- June, Carl H.
- Melenhorst, J. Joseph
- ORCID
- Fraietta, Joseph A.
- Nobles, Christopher L.
- Sammons, Morgan A.
- Lundh, Stefan
- Carty, Shannon A.
- Reich, Tyler J.
- Cogdill, Alexandria P.
- Morrissette, Jennifer J. D.
- Gohil, Mercy
- Kulikovskaya, Irina
- Gupta, Minnal
- Chen, Fang
- Everett, John K.
- Alexander, Katherine A.
- Lin-Shiao, Enrique
- Gee, Marvin H.
- Liu, Xiaojun
- Young, Regina M.
- Wang, Yan
- Xu, Jun
- Jordan, Martha S.
- Levine, Bruce L.
- Zhao, Yangbing
- Kalos, Michael
- Porter, David L.
- Kohli, Rahul M.
- Lacey, Simon F.
- Berger, Shelley L.
- Bushman, Frederic D.
- June, Carl H.
- Melenhorst, J. Joseph
- Venue
- Nature
- Published
- 2018-05-30
- Volume
- 558
- Issue
- 7709
- Pages
- 307-312
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6320248
- OpenAlex
- W2804231581
- Cited by
- 862
- References
- 47
- Citations by year
- 2026: 69 · 2025: 117 · 2024: 126 · 2023: 111 · 2022: 105 · 2021: 116 · 2020: 107 · 2019: 86 · 2018: 25
- FWCI
- 31.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (T32CA009140, R01CA165206, R01CA078831, P01CA214278)
- National Institute of General Medical Sciences (R01GM118501)
- National Institute of Allergy and Infectious Diseases (U01AI104400, K08AI101008, R01AI104400, U19AI117950, R01AI082020, P30AI045008)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- TET2, CD19, chimeric antigen receptor T cells, CAR T-cell therapy, chronic lymphocytic leukemia, DNA methylation, epigenetic reprogramming, T cell differentiation, central memory T cells, T cell expansion, B-cell malignancies
- MeSH terms
- Aged, Alleles, Cell Differentiation, Clinical Trials as Topic, Clone Cells, Humans, Immunotherapy, Male, Mutation, Recombinant Fusion Proteins, T-Lymphocytes, Leukemia, Lymphocytic, Chronic, B-Cell, Antigens, CD19, Transgenes, Adoptive Transfer, Epigenesis, Genetic, 5-Methylcytosine, Dioxygenases, HEK293 Cells
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