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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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Single-cell technologies to dissect heterogenous immune cell therapy products
Mueller, K. P., & Saha, K. (2021) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2021.100343 · Cited by 4
Tumor-intrinsic CD21 expression impacts the response of B-cell malignancy cells to CD19-CAR-T cells
Li, D., Xu, Q., Hu, Y., Wang, W., Xie, S., Zhao, C., & Liu, H. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.5ma0122-474r · Cited by 4
Genome-Edited T Cell Therapies
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Ligon, J. A., Ramakrishna, S., Ceppi, F., Calkoen, F., Diorio, C. J., Davis, K. L., Jacoby, E., Gottschalk, S. M., Schultz, L. M., & Capitini, C. M. (2023) · Transplantation and Cellular Therapy · doi:10.1016/j.jtct.2023.10.012 · Cited by 4
Antibody and cellular immunotherapies for acute lymphoblastic leukemia in adults
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Adaptive Immunity and the Tumor Microenvironment
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HIV-1 transcription dominates over host gene activity at the HIV-1 integration site
Weissman, S., Yeh, Y.-H. J., Viazmenski, M. R., Kim, R., Collora, J. A., Steinhauser, S. F., & Ho, Y. (2025) · mBio · doi:10.1128/mbio.02755-25 · Cited by 3
“…CAR cassette into specific cancer genes can potentiate CAR-T cell therapeutic effect by promoting the persistence of CAR T cells (by insertional activation of BACH2 ) (42) or driving proliferation of specific clones (by insertional disruption of TET2 or insertional activation of VAV1 ) (56, 57).”
CAR-T cell exhaustion in B cell lymphoma: Current status, mechanisms, and potential solutions
Zhao, R., Xia, J., Zheng, Y., Huang, W., Yu, L., & Wang, L. (2025) · Molecular Therapy Oncology · doi:10.1016/j.omton.2025.201099 · Cited by 3
Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms
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Re-balancing immunity with CRISPR-Cas9: Novel strategies for cancer and autoimmune disorders
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CRISPR in clinical oncology: translational advances from molecular diagnostics to therapeutics
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“TET2 and chromatin remodelling factors have likewise been identified as potential targets 130,131 .”
Immune-based therapies in diffuse large B-cell lymphoma
McCurry, D., Flowers, C. R., & Bermack, C. (2023) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2023.2230137 · Cited by 3
“TET2 [106], BATF [107], TOX [108], CBL-B [109]).”
A Pathologist’s Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products
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“27,49,58,66 The potential sources of tumorigenesis within CAR T-cells are host/patient related such as the presence of subclinical cell clones with transformative potential or residual neoplastic cells in the apheresate with risk of transduction.”
Leveraging Vector-Based Gene Disruptions to Enhance CAR T-Cell Effectiveness
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Self-citationChallenges facing CAR T-cell immunotherapy in multiple myeloma
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Peripheral T cell lymphoma following CD19-targeted chimeric antigen receptor T cell therapy
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“A chronic lymphocytic leukemia patient in a clinical trial for CD19 CAR T cell therapy (trial: NCT01029366) exhibited clonal CAR T cell expansion due to retroviral insertion disrupting the TET2 gene [11].”
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T cell TET2 disruption cuts the breaks on antitumor CAR T cell therapy
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Mechanism, Challenges, and Progresses of Chimeric Antigen Receptors T-cell Cancer Therapy
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CAR T cell resistance to oncogenic transformation.
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“Clonal CART cells were characterized by lentiviral insertion of the CAR transgene in the TET2 gene, resulting in its disruption and consequent promotion of CART proliferation (7).”
Self-citationMaurer, K., & Jacobson, C. (2025) · Leukemia and Lymphoma · doi:10.1080/10428194.2025.2460043 · Cited by 4
“One study described a case report of an unusually robust clonal expansion of a single cD19-directed cAR-t clone in a patient with cll [53]. in this case, the lentiviral vector had integrated into the TET2 gene, disrupting its functionality, while the patient’s second TET2 allele harbored a…”
Suleman, S., Alhaque, S., Guo, A. Y., Zhang, H., Payne, A. M., Zahn, M., Fawaz, S., Khalifa, M. S., Jobling, S., Hay, D. C., et al. (2025) · Gene Therapy · doi:10.1038/s41434-025-00550-9 · Cited by 4
Adding chimeric antigen receptor–induced killer cells to the medical oncology shelf
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“Even “safe” lentiviral modification of peripheral T cells can integrate into genetic loci and dramatically change the T cell phenotype (7).”
BackgroundA brief review concerning Chimeric Antigen Receptors T cell therapy
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Self-citationCD4+ chimeric antigen receptor T cells in for the long journey
Chen, A. X., Derrick, E. B., Beavis, P. A., & House, I. G. (2022) · Immunology and Cell Biology · doi:10.1111/imcb.12545 · Cited by 3
“Thus, identifying the lentiviral integration site and its impact on clonal evolution are of significant interest to the field, largely sparked by the observation that a TET2 integration event was responsible for the clonal expansion of CAR T cells in one patient with chronic lymphoblastic leukemia.(15) However, in the…”
BackgroundCellular Therapy in Chronic Lymphocytic Leukemia: Have We Advanced in the Last Decade?
Beyar‐Katz, O., Yehudai‐Ofir, D., & Zuckerman, T. (2023) · Acta Haematologica · doi:10.1159/000534341 · Cited by 4
“For example, disruption of ten-eleven translocation 2 (TET2) can lead to enhanced T-cell memory and high CAR-T cell expansion, albeit with the risk of genomic instability [78, 79].”
BackgroundAdvances in engineering and synthetic biology toward improved therapeutic immune cells
Mai, D., Sheppard, N. C., & Levine, B. L. (2021) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2021.100342 · Cited by 3
Self-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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