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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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“4,5 These concerns are now being closely investigated by the FDA.”
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“86 A recent study correlating the efficacy of BCMA CAR-T cells with the CAR density suggested that a higher CAR density on the surface of T cells, resulting from a greater number of viral integrations, could be predictive of poor outcomes in patients due to high tonic signalling and exhaustion-like…”
Self-citationRodríguez‐Sevilla, J. J., Gañán‐Gómez, I., Kumar, B., Thongon, N., Ma, F., Chien, K. S., Kim, Y. J., Yang, H., Loghavi, S., Tan, R., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58662-0 · Cited by 10
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Cosentino, C., Mouhssine, S., Zucchetto, A., Romano, I. J., Salehi, M., Cappelli, L. V., Iannelli, F., Almasri, M., Maher, N., Fumagalli, L., et al. (2026) · HemaSphere · doi:10.1002/hem3.70322 · Cited by 9
“34,35 In this study, single ‐ cell transcriptomic analysis of T cells from CH+ CLL showed significant upregulation of pathways involved in T ‐ cell activation and proliferation.”
Plasma proteomic and metabolomic signatures of B‐ALL patients during CAR‐T cell therapy
Wu, J., Tang, L., Du, M., Li, C., Kou, H., Jiang, H., Luo, W., Zhang, Y., Huang, Z., Liao, D., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1225 · Cited by 9
Synthesizing a Smarter CAR T Cell: Advanced Engineering of T-cell Immunotherapies
Zhu, I., Piraner, D. I., & Roybal, K. T. (2023) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-22-0962 · Cited by 9
Genome editing approaches for universal chimeric antigen receptor T cells
Mishra, A. K., & Qasim, W. (2024) · EJC Paediatric Oncology · doi:10.1016/j.ejcped.2024.100149 · Cited by 9
“Genome editing to disrupt PRDM1 [46], TET2 [47] and DNMT3A [48] have helped maintain early memory phenotype and improve persistence.”
Daniels, J., & Choi, J. (2021) · Blood · doi:10.1182/blood.2021012641 · Cited by 10
The steep uphill path leading to ex vivo gene therapy for genodermatoses
Palamenghi, M., Luca, M. D., & Rosa, L. D. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00117.2022 · Cited by 10
RETRACTED ARTICLE: Molecular and therapeutic effect of CRISPR in treating cancer
Rodrigo, S., Senasinghe, K., & Quazi, S. (2023) · Medical Oncology · doi:10.1007/s12032-022-01930-6 · Cited by 10
“E TET2 gene a master regulator of hematopoiesis, which commonly gets dysfunction in CLL, and other hematopoietic cancers as inhibit potent CAR T cell properties of immuno-therapy and finding Tet2 negative specific cells via above mechanisms could positively impact on tumor immune response [61, 62].”
RetractedPotency monitoring of CAR T cells
Wang, D., Yang, X., Xella, A., Stern, L. A., & Brown, C. E. (2022) · Methods in cell biology · doi:10.1016/bs.mcb.2022.07.010 · Cited by 9
Functional diversification and dynamics of CAR-T cells in patients with B-ALL
Li, Z., Zhao, L., Zhang, Y., Zhu, L., Mu, W., Ge, T., Jin, J., Tan, J., Cheng, J., Wang, J., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113263 · Cited by 10
Decoding Clonal Hematopoiesis: Emerging Themes and Novel Mechanistic Insights
Pendse, S., & Loeffler, D. (2024) · Cancers · doi:10.3390/cancers16152634 · Cited by 8
“Besides these changes in differentiation, the disruption of either Dnmt3a [87] or Tet2 [88] was found to promote the therapeutic efficacy of CAR T cells, suggesting that these mutant CAR T cells do not become exhausted and maintain their capacity to proliferate.”
BackgroundVijenthira, A., Volpe, V. O., Sekar, A., Azevedo, R. S., Mikhaleva, M., Gibson, C. J., Martindale, S. P., Fardoun, R., Tyekucheva, S., Ren, Y., et al. (2024) · Blood Advances · doi:10.1182/bloodadvances.2024013414 · Cited by 10
Yan, W., Xiong, Y., Lv, R., Du, C., Yu, T., Zhang, S., Sui, W., Deng, S., Xiao, J., Xu, Y., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010080 · Cited by 8
Pilocytic astrocytoma in a child with spinal muscular atrophy treated with onasemnogene abeparvovec
Holzwarth, D., Calaminus, G., Friese, J., Sejersen, T., Büning, H., John-Neek, P., Bastone, A. L., Rothe, M., Mansfield, K. G., Libertini, S., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.02.025 · Cited by 8
“38,39 After transduction, rAAV vectors persist primarily as episomal DNA within the cell.”
Ismail, A., Khormi, M. A., Mawkili, W., Albaqami, A., Areshi, S. M., Aborasain, A. M., Hegazy, M. M., Amin, A. H., & Abo-Zaid, M. A. (2025) · Experimental Hematology · doi:10.1016/j.exphem.2025.104762 · Cited by 9
Rondeau, V., Bansal, S., Buttigieg, M. M., Zeng, A. G. X., Chan, D. Y., Chan‐Seng‐Yue, M., Liqing, J., McLeod, J. L., Kates, M., Donato, E., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-3329 · Cited by 12
Pesini, C., Gil-Bellido, M., Millán, L., Oñate, C., Calvo-Pérez, A., Santiago, L., Iglesias, E., Bernal, J. P., Araujo‐Voces, M., Artigas, L. P., et al. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-012706 · Cited by 10
“32 Given the recurrence rate of myelofibrosis (10%–30”
Clonal Hematopoiesis: Origins and determinants of evolution
Mendez, L., & Patnaik, M. M. (2023) · Leukemia Research · doi:10.1016/j.leukres.2023.107076 · Cited by 8
Applications of single‐cell omics for chimeric antigen receptor T cell therapy
Ghaffari, S., Saleh, M., Akbari, B., Ramezani, F. M., & Mirzaei, H. R. (2023) · Immunology · doi:10.1111/imm.13720 · Cited by 8
“…CAR transgene integration into the CBL gene greatly expanded the subclones until they constituted almost half of the white blood cell population [57], while another study showed how 94% of CAR T cells 2 months post-infusion originated from one clone whose TET2 was disrupted by CAR transgene [58].”
BackgroundKlapwijk, J. C., Río-Espínola, A. D., Libertini, S., Collin, P., Fellows, M. D., Jobling, S., Lynch, A. M., Martus, H., Vickers, C. A., Zeller, A., et al. (2024) · Human Gene Therapy · doi:10.1089/hum.2024.033 · Cited by 9
“82 – 84 Similarly, clonal expansions have been observed after SIN LV gene therapy in hematopoietic stem cells (HSCs) associated with integration in HMGA2 in one beta-thalassemia patient and multiple SCID patients.”
Self-citationGene therapy strategies for RAG1 deficiency: Challenges and breakthroughs
Gilioli, G., Lankester, A. C., de Kivit, S., Staal, F. J. T., & de Bruin, L. M. O. (2024) · Immunology Letters · doi:10.1016/j.imlet.2024.106931 · Cited by 8
Enabling drug discovery and development through single-cell imaging
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“a CLL patient treatedwith CD19 CAR-T therapy [3].”
BackgroundApproaches of T Cell Activation and Differentiation for CAR-T Cell Therapies
Schwab, R. D., Bedoya, D. M., King-Peoples, T. R., Levine, B. L., & Posey, A. D. (2019) · Methods in molecular biology · doi:10.1007/978-1-0716-0146-4_15 · Cited by 9
Self-citationp38 Kinase: A Key Target for Driving Potent T Cells for Adoptive Immunotherapy
Chan, J. D., Beavis, P. A., & Darcy, P. K. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.05.012 · Cited by 8
Challenges and Prospects for Designer T and NK Cells in Glioblastoma Immunotherapy
Arnesen, V. S., Navarro, A. G., & Chekenya, M. (2021) · Cancers · doi:10.3390/cancers13194986 · Cited by 8
TET2 regulates immune tolerance in chronically activated mast cells
Rigo, R., Chelbi, R., Agopian, J., Letard, S., Griffon, A., Ghamlouch, H., Vernerey, J., Ladopoulos, V., Voisset, E., Sepulveda, P. D., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.154191 · Cited by 8
“TET2 mutation in CAR T cells (51, 52) and provides additional rationale for targeting TET2 and SOCS for immune therapies.”
BackgroundWang, J., Shen, K., Mu, W., Li, W., Zhang, M., Zhang, W., Li, Z., Ge, T., Zhu, Z., Zhang, S., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.873789 · Cited by 9
“Third, next-generation sequencing (NGS) studies suggested that transgenes integrated into the TET2 locus may also occur in CAR T-cell therapy (20).”
BackgroundResultChimeric Antigen Receptor T-Cell Therapy and Hematopoiesis
Reinhardt, B., Lee, P. C., & Sasine, J. P. (2023) · Cells · doi:10.3390/cells12040531 · Cited by 9
Chemical probes for spatially resolved measurement of active enzymes in single cells
Li, G., & Moellering, R. E. (2019) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2019.06.017 · Cited by 6
“This loss of information is notable, as cellular heterogeneity can dynamically shift in response to a multitude of input signals, and has been shown to be important in a wide range of biological contexts, including oncogenesis(Reya, Morrison, Clarke, & Weissman, 2001), antibiotic resistance(Allison, Brynildsen, & Coll…”
BackgroundCAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies
Mi, J., Xu, J., Zhou, J., Zhao, W., Zhu, C. H., Melenhorst, J. J., & Chen, S. (2021) · Frontiers of Medicine · doi:10.1007/s11684-021-0904-z · Cited by 8
“Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, Cogdill AP, Morrissette JJD, DeNizio JE, Reddy S, Hwang Y, Gohil M, Kulikovskaya I, Nazimuddin F, Gupta M, Chen F, Everett JK, Alexander KA, Lin-Shiao E, Gee MH, Liu X, Young RM, Ambrose D, Wang Y, Xu J, Jordan MS, Marcucci KT, Levine BL, Garcia KC, Zhao…”
BackgroundSelf-citationc-Jun Overexpressing CAR-T Cells are Exhaustion-Resistant and Mediate Enhanced Antitumor ActivityPreprint
Lynn, R. C., Weber, E. W., Gennert, D. G., Sotillo, E., Xu, P., Good, Z., Anbunathan, H., Jones, R. C., Tieu, V., Granja, J. M., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/653725 · Cited by 8
McCutcheon, S. R., Swartz, A. M., Brown, M. C., Barrera, A., Amador, C. M., Siklenka, K., Humayun, L. L., Isaacs, J. M., Reddy, T. E., Nair, S. K., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.01.538906 · Cited by 8
Photothermal nanofibers enable macromolecule delivery in unstimulated human T cells
Berdecka, D., Minsart, M., Lu, T., Punj, D., Rycke, R. M. D., Nikolić, M., Bolea‐Fernandez, E., Vanhaecke, F., Xiong, R., Smedt, S. C. D., et al. (2023) · Applied Materials Today · doi:10.1016/j.apmt.2023.101991 · Cited by 7
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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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