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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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Somatic mutations and T-cell clonality in patients with immunodeficiency
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“Although the function of the discovered mutations was not analyzed in our study, previous studies by us and others suggest that somatic mutations may alter the phenotype and function of mutated T cells.(16,40) Interestingly, Fraietta et al.”
BackgroundResultHerbrich, S. M., Anandhan, S., Andrewes, S. W., Chaib, M., Nagarajan, A., Guan, B., Tang, D. N., Gandhi, N., Gilliam, J., Radovich, M., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.09.011 · Cited by 31
Mata, M., & Gottschalk, S. M. (2019) · Drugs · doi:10.1007/s40265-019-01071-7 · Cited by 25
Understanding and Modulating Immunity With Cell Reprogramming
Pires, C. F., Rosa, F. A., Kurochkin, I., & Pereira, C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02809 · Cited by 25
“In addition, loss of the epigenetic enzyme TET2 was shown to reduce T cell differentiation and promote expansion of potent memory T cells (235).”
BackgroundKim, D., Park, G., Huuhtanen, J., Lundgren, S., Khajuria, R. K., Hurtado, A. M., Muñoz‐Calleja, C., Cardeñoso, L., de Soria, V. G.-G., Chen‐Liang, T. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16115-w · Cited by 27
Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential
Maes, K., Mondino, A., Lasarte, J. J., Agirre, X., Vanderkerken, K., Prósper, F., & Breckpot, K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.652160 · Cited by 25
Peng, M., Rayana, N. P., Dai, J., Sugali, C. K., Baidouri, H., Suresh, A., Raghunathan, V. K., & Mao, W. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2022.109097 · Cited by 24
Epigenetic Perspective of Immunotherapy for Cancers
Keshari, S., Barrodia, P., & Singh, A. K. (2023) · Cells · doi:10.3390/cells12030365 · Cited by 26
Xiao, C., Fan, T. T., Zheng, Y., Tian, H., Deng, Z., Liu, J., Li, C., & He, J. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005693 · Cited by 25
The crossroads of cancer therapies and clonal hematopoiesis
Singh, A., & Balasubramanian, S. K. (2024) · Seminars in Hematology · doi:10.1053/j.seminhematol.2024.01.006 · Cited by 28
Arunachalam, A. K., Grégoire, C., de Oliveira, B. C., & Melenhorst, J. J. (2024) · Blood Reviews · doi:10.1016/j.blre.2024.101241 · Cited by 27
Self-citationSynthetic macromolecular switches for precision control of therapeutic cell functions
Teixeira, A. P., & Fussenegger, M. (2024) · Nature Reviews Bioengineering · doi:10.1038/s44222-024-00235-9 · Cited by 28
“This results in heterogenous cell populations with variable CAR integration sites, potentially affecting T cell proliferation and therapeutic efficacy 159,160 .”
Emerging T-cell lymphomas after CAR T-cell therapy
Braun, T., Kuschel, F., Reiche, K., Merz, M., & Herling, M. (2025) · Leukemia · doi:10.1038/s41375-025-02574-x · Cited by 27
“In agreement, TET2 disruption due to CAR transgene integration into one TET2 allele, combined with an additional hypomorphic TET2 mutation in the other allele, enhanced the therapeutic ef fi cacy of CD19-directed CAR-T cells in a reported case [18].”
A decade of CAR T cell evolution
Maus, M. V. (2022) · Nature Cancer · doi:10.1038/s43018-022-00347-4 · Cited by 24
Frankiw, L. S., Singh, A. S., Peters, C. W., Comı́n-Anduix, B., Berent-Maoz, B., Macabali, M. H., Shammaie, K., Quiros, C., Kaplan‐Lefko, P. J., Baselga-Carretero, I., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-006930 · Cited by 24
Massively parallel CRISPR off-target detection enables rapid off-target prediction model building
Tian, R., Cao, C., He, D., Dong, D., Sun, L., Liu, J., Chen, Y., Wang, Y., Huang, Z., Li, L., et al. (2023) · Med · doi:10.1016/j.medj.2023.05.005 · Cited by 25
Self-citationH 2 S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response
Oberholtzer, N., Chakraborty, P., Kassir, M. F., Dressman, J., Das, S., Mills, S., Comte-Walters, S., Gooz, M., Choi, S., Parikh, R. Y., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp1152 · Cited by 24
“However, recent studies have shown that reduced Tet2 expression results in the improved function of CD19 CAR-engineered T cells ( 31 ).”
Fix, S. M., Jazaeri, A. A., & Hwu, P. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1083 · Cited by 25
“Fraietta and colleagues (106) made the serendipitous observation that lentiviral integration of a CD19-directed CAR construct in the TET2 gene was associated with remission in a patient with chronic lymphocytic leukemia.”
BackgroundEarly-phenotype CAR-T cells for the treatment of pediatric cancers
Meyran, D., Terry, R. L., Zhu, J. J., Haber, M., Ziegler, D. S., Ekert, P. G., Trapani, J. A., Darcy, P. K., & Neeson, P. J. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.07.018 · Cited by 24
Therapeutic roles of CAR T cells in infectious diseases: Clinical lessons learnt from cancer
Mohammadi, M., Akhoundi, M., Malih, S., Mohammadi, A., & Sheykhhasan, M. (2022) · Reviews in Medical Virology · doi:10.1002/rmv.2325 · Cited by 24
“observed that by knocking down the methylcytosine dioxygenase TET2 gene, the expansion and efficacy of CAR T cells improved.(118) Moreover, in HIV therapy, the temporary persistence of infused CAR T cells may occur due to”
MethodInterpreting the B-cell receptor repertoire with single-cell gene expression using Benisse
Zhang, Z., Chang, W. Y., Wang, K., Yang, Y., Wang, X., Yao, C., Wu, T., Wang, L. L., & Wang, T. (2022) · Nature Machine Intelligence · doi:10.1038/s42256-022-00492-6 · Cited by 25
Current progress in CAR‑T cell therapy for tumor treatment (Review)
Chen, L., Xie, T., Wei, B., & Di, D.-L. (2022) · Oncology Letters · doi:10.3892/ol.2022.13478 · Cited by 25
“There is a specific error probability in the production of CAR‐T cells using the lentiviral packaging system; it has been reported that the TET2 gene is integrated randomly into CAR and this integration endows CAR‐T cells with enhanced proliferation and anti‐tumor ability, indicating that the TET2 gene may help to imp…”
MethodMurphy, L. A., Marians, R. C., Miller, K. R., Brenton, M. D., Mallo, R., Kohler, M. E., Fry, T. J., & Winters, A. C. (2022) · Cytotherapy · doi:10.1016/j.jcyt.2022.09.004 · Cited by 24
Genome Editing in Engineered T Cells for Cancer Immunotherapy
Bonini, C., Chapuis, A. G., Hudecek, M., Guedan, S., Magnani, C. F., & Qasim, W. (2023) · Human Gene Therapy · doi:10.1089/hum.2023.128 · Cited by 29
“138 Although TET2 is a tumor-suppressor gene and a master regulator of blood cell formation, its disruption alone has not been associated with overt oncogenesis.”
Engineering T Cells to Treat Cancer: The Convergence of Immuno-Oncology and Synthetic Biology
Choe, J. H., Williams, J. Z., & Lim, W. A. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033657 · Cited by 23
Chen, L., Xu, B., Long, X., Gu, J., Lou, Y., Wang, D., Cao, Y., Wang, N., Li, C., Wang, G., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000364 · Cited by 23
Self-citationZhou, Z.-K., Zhang, G., Xu, Y., Yang, S., Wang, J.-J., Li, Z.-R., Peng, F., & Lu, Q. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217083 · Cited by 21
Opportunities and Challenges for Antibodies against Intracellular Antigens
Yang, X., Xie, S., Yang, X., Jumbo, J. C. C., Hou, X., Tang, Z., Yao, H., Mo, F., Yin, S., Liu, A., et al. (2019) · Theranostics · doi:10.7150/thno.35486 · Cited by 22
“Fraietta and colleagues reported that due to the proliferation of a single CAR-T cell, a patient with chronic lymphocytic leukemia (CLL) treated with CAR-T cells in 2013 was relieved and remains cancer-free for over 5 years, and that the CAR-T cells are still present in his immune system [229].”
BackgroundMondello, P., Ansell, S. M., & Nowakowski, G. S. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.826594 · Cited by 23
“Additionally, loss of TET2 significantly enhanced immune response to CAR T cell therapy and suppressed tumor growth (Pan et al., 2017; Fraietta et al., 2018).”
BackgroundBiological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer
Ferrer, G., Álvarez‐Errico, D., & Esteller, M. (2022) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djac088 · Cited by 23
CHIPing away the progression potential of CHIP: A new reality in the making
Xie, Z., & Zeidan, A. M. (2022) · Blood Reviews · doi:10.1016/j.blre.2022.101001 · Cited by 22
Delivery of macromolecules in unstimulated T cells by photoporation with polydopamine nanoparticles
Berdecka, D., Harizaj, A., Goemaere, I., Punj, D., Goetgeluk, G., Munter, S. D., Keersmaecker, H. D., Boterberg, V., Dubruel, P., Vandekerckhove, B., et al. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.01.047 · Cited by 22
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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