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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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Clonal hematopoiesis in myeloid malignancies and solid tumors
Cai, X., Bowman, R. L., & Trowbridge, J. J. (2025) · Nature Cancer · doi:10.1038/s43018-025-01014-0 · Cited by 18
“Similarly, TET2 -deficient CAR-T cells in a patient with relapsed and refractory chronic lymphocytic leukemia had altered molecular signatures of T cell differentiation, displayed a central memory phenotype, exerted efficient anticancer effects and induced complete remission in the patient 113 .”
Clonal haematopoiesis to clonal cytopenias: unravelling disease evolution over time
Kirschner, K., Kusne, Y. N., Cargo, C. A., & Patnaik, M. M. (2025) · The Lancet Haematology · doi:10.1016/s2352-3026(25)00137-1 · Cited by 16
Cancer vaccines: Discovery, development, and challenges for clinical translation
Zhang, Z., Yao, S., Wang, Y., Luo, K., Amiji, M. M., & Anderson, K. C. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123615 · Cited by 15
Self-citationEpigenetic engineering for optimal chimeric antigen receptor T cell therapy
Ito, Y., & Kagoya, Y. (2022) · Cancer Science · doi:10.1111/cas.15541 · Cited by 14
Beyond BCMA: the next wave of CAR T cell therapy in multiple myeloma
Miller, K. C., Hashmi, H., & Rajeeve, S. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1398902 · Cited by 19
“…anti-CD19 CAR T cell therapy for B cell lymphomas has identi fi ed the importance of CAR T cell immunophenotypic characteristics, including propensity toward immune exhaustion and complex signaling cross-talk within the tumor microenvironment as major determinants of therapeutic response (41 – 50).”
BackgroundNaik, S., Velasquez, M. P., & Gottschalk, S. M. (2024) · Haematologica · doi:10.3324/haematol.2023.283817 · Cited by 15
Kim, H. K., Choi, Y., Kim, K. H., Byun, Y., Kim, T. H., Kim, J. H., An, S. H., Bae, D., Choi, M. K., Lee, M., et al. (2024) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12508 · Cited by 19
Micro but mighty—Micronutrients in the epigenetic regulation of adaptive immune responses*
Chen, H., Hsu, M., & Lio, C. J. (2021) · Immunological Reviews · doi:10.1111/imr.13045 · Cited by 17
CAR T-cell Therapy Meets Clonal Hematopoiesis
Uslu, U., & June, C. H. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-22-0067 · Cited by 15
Self-citationNew insights on potency assays from recent advances and discoveries in CAR T-cell therapy
Shao, L., Zheng, Y., Somerville, R. P. T., Stroncek, D. F., & Jin, P. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1597888 · Cited by 16
Liu, G., Tian, X., Wang, Q., Xu, S., Jiang, Y., Gao, Y., & Wu, Y. (2025) · Science Advances · doi:10.1126/sciadv.adx9221 · Cited by 16
“Similarly, Fraitta et al. ( 19 ) reported that TET2 - deficient CD19 CAR T cells displayed a remodeled epigenetic landscape, redi-recting their differentiation trajectory toward sustained antitumor activity and inducing remission in patients with chronic lymphocytic leukemia.”
Lentiviral Vectors: From Wild-Type Viruses to Efficient Multi-Functional Delivery Vectors
Arrasate, A., Lopez-Robles, C., Zuazo, M., Baños-Mateos, S., Martín, C., Lamsfus‐Calle, A., & Fertin, M. J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178497 · Cited by 14
“Indeed, there are certain cases of clonal expansion that were non-malignant and still resulted in disease remission [131,132].”
Next-generation T cell immunotherapy: overcoming exhaustion, senescence, and suppression
Li, G., Li, D., & Zhu, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1662145 · Cited by 17
“Deleting the DNA demethylase TET2 signi fi cantly extends the lifespan of CAR-T cells and enhances their tumor-killing capacity (112).”
BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells
Hu, T., Zhu, Z., Ying, L., Wizzard, S., Hoar, J., Shinde, S. S., Yihunie, K. D., Yao, C., & Wu, T. (2026) · Nature Immunology · doi:10.1038/s41590-025-02388-0 · Cited by 16
Translational considerations for immunotherapy clinical trials in pediatric neuro-oncology
Foster, J., Alonso, M. M., Sayour, E. J., Davidson, T. B., Persson, M. L., Dun, M. D., Kline, C., Mueller, S., Vitanza, N. A., & van der Lugt, J. (2023) · Neoplasia · doi:10.1016/j.neo.2023.100909 · Cited by 14
Yang, Z., Liu, L., Zhu, Z., Hu, Z., Liu, B., Gong, J., Jin, Y., Luo, J., Deng, Y., Jin, Y., et al. (2024) · Advanced Science · doi:10.1002/advs.202304501 · Cited by 15
Advances in breast cancer research using CRISPR/Cas9 system
Eskandari, F., Aali, M., Hadisadegh, S. N., & Azadeh, M. (2024) · Nano Select · doi:10.1002/nano.202400015 · Cited by 18
Guerrero-Murillo, M., Rill, A., Trincado, J. L., Bataller, Á., Ortiz‐Maldonado, V., Benítez‐Ribas, D., Español‐Rego, M., González‐Navarro, E. A., Martínez‐Cibrián, N., Marchese, D., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101803 · Cited by 14
T Cell Receptor Engineered Lymphocytes for Cancer Therapy
Rollins, M. R., Spartz, E. J., & Stromnes, I. M. (2020) · Current Protocols in Immunology · doi:10.1002/cpim.97 · Cited by 15
Fu, W., Lei, C., Wang, C., Ma, Z., Li, T. X., Lin, F., Mao, R., Zhao, J., & Hu, S. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-022-00895-1 · Cited by 14
“(4) Clonal expansion questions the long-term safety of TET2-modified CAR T cells; additional safety-control methods, such as suicide gene switches, may be needed.”
BackgroundFalini, L., Venanzi, A., Tini, V., Innocente, A., Ballanti, S., Saldi, S., Sivolella, S., Pierini, A., Aristei, C., Tiacci, E., et al. (2022) · Haematologica · doi:10.3324/haematol.2022.281351 · Cited by 14
Engineering T cells for immunotherapy of primary human hepatocellular carcinoma
Galva, L. D. C., Cai, L., Shao, Y., & He, Y. (2020) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2020.01.002 · Cited by 14
Next-generation CAR T cells to overcome current drawbacks
Lundh, S. M., Maji, S., & Melenhorst, J. J. (2020) · International Journal of Hematology · doi:10.1007/s12185-020-02923-9 · Cited by 15
Self-citationT cell receptor therapy against melanoma—Immunotherapy for the future?
Winge-Main, A., Wälchli, S., & Inderberg, E. M. (2020) · Scandinavian Journal of Immunology · doi:10.1111/sji.12927 · Cited by 14
“To date there have been no reported transformation events following viral transfer in melanoma trials, but there remains possibility of viral-induced gene disruption (37).”
BackgroundCRISPR Takes the Front Seat in CART-Cell Development
Manriquez-Roman, C., Siegler, E. L., & Kenderian, S. S. (2021) · BioDrugs · doi:10.1007/s40259-021-00473-y · Cited by 15
Chimeric Antigen Receptor T-cell Therapy in Cancer: A Critical Review
Sharma, R., Suravarjhula, L., Banerjee, M., Kumar, G., & Kumar, N. (2023) · Current Drug Research Reviews · doi:10.2174/2589977515666230220092125 · Cited by 13
Engineering enhanced chimeric antigen receptor-T cell therapy for solid tumors
Neeser, A., Ramasubramanian, R., Wang, C., & Ma, L. (2023) · Immuno-Oncology Technology · doi:10.1016/j.iotech.2023.100385 · Cited by 13
Innate immune response restarts adaptive immune response in tumors
Li, W.-S., Zhang, Q., Li, Q., Liu, S.-Y., Yuan, G.-Q., & Pan, Y.-W. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1260705 · Cited by 14
Epigenome-Driven Strategies for Personalized Cancer Immunotherapy
Rocha, G. I. Y., Gomes, J. E. M., Leite, M. L., da Cunha, N. B., & Costa, F. F. (2023) · Cancer Management and Research · doi:10.2147/cmar.s272031 · Cited by 15
“7,96,100,101 One of the most important roles of DNMTis is the upregulation of immune signaling in cancer and, in this context, the main route by which this goal is achieved is the viral mimicry pathway.”
BackgroundCorrea, L. O., Jankowski, S. E., Hong, H. S., Armas, N. D., Vijendra, A. I., Reynolds, M. B., Fogo, G. M., Awad, D., Dils, A. T., Inoki, K. A., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114156 · Cited by 14
Self-citationLemmens, M., Dorsheimer, L., Zeller, A., & Dietz, Y. (2024) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2024.503767 · Cited by 15
Chabannon, C., Ruggeri, A., Montoto, S., van Biezen, A., van der Werf, S. M., Markslag, A., Sánchez‐Ortega, I., de la Cámara, R., Ljungman, P. T., Mohty, M., et al. (2024) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2024.101557 · Cited by 15
Bouziana, S. D., & Bouzianas, D. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179518 · Cited by 12
“This occurred via the integration of an LV either in the TET2 gene, which regulates haematopoiesis and T-cell differentiation, or in the CBL gene, which regulates T-cell responses [64,65].”
The next innovations in chimeric antigen receptor T cell immunotherapies for cancer
Anupindi, K., Malachowski, J., Hodson, I., Zhu, D., June, C. H., & Levine, B. L. (2025) · Cytotherapy · doi:10.1016/j.jcyt.2025.05.010 · Cited by 13
Self-citationLes CAR-T cells, des cellules tueuses spécifiques d’antigènes tumoraux
Catros, V. (2019) · médecine/sciences · doi:10.1051/medsci/2019067 · Cited by 22
TEG001 Insert Integrity from Vector Producer Cells until Medicinal Product
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Enhancing CAR T cell efficacy: the next step toward a clinical revolution?
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“T cells and altered their differentiation pattern [40].”
Background
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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