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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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Decade-long remissions of leukemia sustained by the persistence of activated CD4+ CAR T-cellsPreprint
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Self-citationIL-12 Signaling Promotes TET2-Mediated DNA Demethylation During CD8 T Cell Effector DifferentiationPreprint
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“Genome integration also has the risk of unwanted mutations, raising safety concerns for certain applications such as adoptive cell therapy (Fraietta et al., 2018; Milone and O’Doherty, 2018; Ranzani et al., 2013).”
BackgroundEpigenetic engineering empowers T cells
Tandel, J., & Gill, S. I. (2022) · Blood · doi:10.1182/blood.2021015016 · Cited by 1
Safety of genetically modified T cells.
Maus, M. V. (2022) · Blood · doi:10.1182/blood.2022016334 · Cited by 1
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Genetics and Epigenetics of Type 1 Diabetes Self-Reactive T CellsPreprint
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Somatic TYK2 activating mutations in tumor-infiltrating T cells promote anti-cancer immunityPreprint
Li, Z., Hsieh, M.-H., Arutyunova, A., Evans, J., Liu, T., Lawson, A. R. J., Nicola, P. A., Kildisiute, G., Machado, H. E., Kawam, A. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.13.682217 · Cited by 1
A CHIP mutation to battle cancer: potential or hazard for cardiovascular disease?
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Gene Transfer to HSCs: Finding the Leukemia in Murine Leukemia Viruses
Cornetta, K. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.05.003
“More recently, clonal expansion in a T cell modified with a chimeric antigen receptor (CAR-T) protocol resulted from insertional disruption of one methylcystosine dioxygenase TET2 allele in an individual with a hypomorphic mutation in the second TET2 allele.(12) To date, these individuals have not developed malignancy.”
BackgroundKammula, U. S., & Lotze, M. T. (2018) · Springer eBooks · doi:10.1007/978-3-319-46029-1_36-1
Park, G., Kim, D., 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. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/747196
Assessment of memory formation by metabolically engineered antigen-specific CD8 T cells
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Orthotopic editing of T-cell receptors
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The non-viral production of Chimeric Antigen Receptor T-cells for B-cell haematological malignancies
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Synthetic Cellular Immunity based on CAR repertoire for Human ImmunotherapyPreprint
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Synthetic biology-based optimization of T cell immunotherapies for cancer
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Self-citationKammula, U. S., & Lotze, M. T. (2020) · Springer eBooks · doi:10.1007/978-3-030-05070-2_36
Genome Editing Applications in Cancer T Cell Therapy
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“Genetic depletion of Tet could impair chromatin accessibility and perturb the binding of 51 transcription factors (TFs) to their genomic targets in cells of the immune systems, including B cells, T 52 cells and macrophages (11-14).”
BackgroundHarjes, U. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0039-y
Wang, C., Silva, M., & Ma, L. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813886-1.00011-5
Klonale Hämatopoese – Bedeutung für die Zelltherapie
Teipel, R., Bonin, M. V., Stölzel, F., Schetelig, J., Thiede, C., & Bornhäuser, M. (2022) · Die Innere Medizin · doi:10.1007/s00108-022-01403-y
Clinical application of cell‐based therapies opportunities and challenges
Gao, J., & Wu, D. (2022) · Clinical and Translational Discovery · doi:10.1002/ctd2.110
Modeling and Simulation of CAR T cell Therapy in Chronic Lymphocytic Leukemia PatientsPreprint
Nukala, U., Messan, M. R., Yogurtcu, O. N., Sauna, Z. E., & Yang, H. (2022) · medRxiv · doi:10.1101/2022.12.01.22282976
“Complete Remission Patients: (Patient-UPN1, UPN2, UPN10): Longitudinal IL-6 concentration data for Patients UPN1, UPN2 were obtained from Supplementary Table S2 and S4 (reference [9]) and data for Patient UPN10 were extracted from Fig 1b (reference [10]) using WebPlotDigitizer (https://automeris.”
MethodKlonale Hämatopoese und solide Neoplasien
Arends, C. M., & Damm, F. (2023) · Wiener klinisches Magazin · doi:10.1007/s00740-022-00472-x
Luan, R., & Deng, B. (2023) · Hematology and Oncology Discovery · doi:10.15212/hod-2022-0009
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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