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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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“In the present study, we found that large clonal populations of vector-modified T cells were uncommon, with the largest, the previously reported TET2 case 20 , involving a participant with a pre-existing mutation in the other allele, likely contributing to the extreme response.”
InfluentialSelf-citationiGUIDE: an improved pipeline for analyzing CRISPR cleavage specificity
Nobles, C. L., Reddy, S. G., Salas-McKee, J., Liu, X., June, C. H., Melenhorst, J. J., Suhoski, M. M., Zhao, Y., & Bushman, F. D. (2019) · Genome biology · doi:10.1186/s13059-019-1625-3 · Cited by 82
“[22] for comparison—HIV favors integration in active transcription units, which is reflected in the integration site preferences [23–25].”
BackgroundSelf-citationBaxter, A. E., Huang, H., Giles, J. R., Chen, Z., Wu, J. E., Drury, S., Tuite-Dalton, K. A., Park, S. L., Torres, L., Simone, B. W., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.05.008 · Cited by 83
Self-citationMcCutcheon, S. R., Swartz, A. M., Brown, M. C., Barrera, A., Amador, C. M., Siklenka, K., Humayun, L. L., ter Weele, M. A., Isaacs, J. M., Reddy, T. E., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01554-0 · Cited by 89
“Genetic disruption of both TET2 and DNMT3A , which encode for proteins that regulate DNA methylation in opposite directions, can improve the therapeutic potential of T cells 19,20 .”
BackgroundCAR T-Cells in Multiple Myeloma: State of the Art and Future Directions
Rodríguez‐Lobato, L. G., Ganzetti, M., de Larrea, C. F., Hudecek, M., Einsele, H., & Danhof, S. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01243 · Cited by 88
“However, in the case of a patient with chronic lymphocytic leukemia receiving CD19 CAR T-cells, a clonal expansion of a single CAR T-cell with biallelic TET2 dysfunction was reported (207).”
BackgroundCellular and molecular waypoints along the path of T cell exhaustion
Lan, X., Zebley, C. C., & Youngblood, B. (2023) · Science Immunology · doi:10.1126/sciimmunol.adg3868 · Cited by 87
Allogeneic CAR T cell therapies for leukemia
Qasim, W. (2019) · American Journal of Hematology · doi:10.1002/ajh.25399 · Cited by 86
“It may be possible to support enhanced T cell expansion and persistence by targeting integration sites associated with clonal dominance in in past patients who were successfully treated.(38) Finally, direct chemical base modification offers is now being investigated whereby base editors (BE) comprising an inactive for…”
BackgroundSurmounting the obstacles that impede effective CAR T cell trafficking to solid tumors
Donnadieu, E., Dupré, L., Pinho, L. G., & Cotta-de-Almeida, V. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.1mr0520-746r · Cited by 85
Xu, J., Wang, B., Yu, S., Chen, S., Yang, S., Liu, R., Chen, L., Hou, J., Chen, Z., Zhao, W., et al. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01530-z · Cited by 89
“This has been observed by both our previous study and that of Fraietta’s study [37, 38], in which, acquired TET2 mutations identified in elderly MM and CLL promoted CAR T expansion.”
ResultSelf-citationCellular kinetics: A clinical and computational review of CAR-T cell pharmacology
Qi, T., McGrath, K. V., Ranganathan, R., Dotti, G., & Cao, Y. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114421 · Cited by 80
Ibrahim, A., Abdalsalam, N. M. F., Liang, Z., Tariq, H. K., Li, R., Afolabi, L. O., Rabiu, L., Chen, X., Xu, S., Xu, Z., et al. (2025) · Cancer Gene Therapy · doi:10.1038/s41417-025-00886-9 · Cited by 89
Clonal hematopoiesis and inflammation – the perpetual cycle
Avagyan, S., & Zon, L. I. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.12.001 · Cited by 79
Next Generation CAR T Cells for the Immunotherapy of High-Grade Glioma
Petersen, C. T., & Krenciute, G. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00069 · Cited by 85
CAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success
Long, K. B., Young, R. M., Boesteanu, A. C., Suhoski, M. M., Melenhorst, J. J., Lacey, S. F., Degaramo, D. A., Levine, B. L., & Fraietta, J. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02740 · Cited by 80
“Furthermore, TET2-disrupted lymphocytes exhibited a predominantly TCM phenotype at the peak of the anti-tumor response (76).”
BackgroundSelf-citationThe forces driving clonal expansion of the HIV-1 latent reservoir
Liu, R., Simonetti, F. R., & Ho, Y. (2020) · Virology Journal · doi:10.1186/s12985-019-1276-8 · Cited by 79
“In another example, lentiviral vectors carrying the chimeric antigen receptor (CAR) cassette in the treatment of chronic lymphocytic leukemia integrated into the intron of the tumor suppressor gene TET2, disrupted TET2 regulatory region and led to a dominant clone (94% at the peak of response) in vivo [92].”
BackgroundMorton, L. T., Reijmers, R. M., Wouters, A. K., Kweekel, C., Remst, D. F. G., Pothast, C. R., Falkenburg, J. H. F., & Heemskerk, M. H. M. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.10.001 · Cited by 77
CRISPR/Cas: From Tumor Gene Editing to T Cell-Based Immunotherapy of Cancer
Azangou‐Khyavy, M., Ghasemi, M., Khanali, J., Boroomand-Saboor, M., Jamalkhah, M., Soleimani, M., & Kiani, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.02062 · Cited by 80
“Studies have confirmed that knocking down TET2, a tumor suppressor gene, leads to epigenetic and phenotypic alterations in T cells, which can improve clinical results (147).”
BackgroundMethodvan der Stegen, S. J. C., Lindenbergh, P. L., Petrovic, R. M., Xie, H., Diop, M. P., Alexeeva, V., Shi, Y., Mansilla‐Soto, J., Hamieh, M., Eyquem, J., et al. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-022-00915-0 · Cited by 79
Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion
Lamarche, C., Ward‐Hartstonge, K. A., Tian, M., Lin, D. T. S., Huang, Q. B., Brown, A., Edwards, K., Novakovsky, G., Qi, C. N., Kobor, M. S., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2219086120 · Cited by 87
“This state of functional exhaustion can be manipulated by limiting the activity of signaling pathways and altering the epigenetic program and/or metabolic pathways (8, 12, 15–17).”
Epigenetic strategies to boost CAR T cell therapy
Akbari, B., Ghahri-Saremi, N., Soltantoyeh, T., Hadjati, J., Ghassemi, S., & Mirzaei, H. R. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.08.003 · Cited by 79
Integrative multi-omics approaches to explore immune cell functions: Challenges and opportunities
Wang, X., Dian, F., Yang, Y., Gimple, R. C., & Zhou, S. (2023) · iScience · doi:10.1016/j.isci.2023.106359 · Cited by 87
“101 Although CAR T cells are typically polyclonal with random integration of lentiviral constructs throughout the genome, in this case, 94% of CAR T cells were monoclonal at the peak of the patient’s responses, and derived from T cells with a lentiviral integration disrupting TET2 genes.”
CRISPR/Cas9: A Powerful Strategy to Improve CAR-T Cell Persistence
Wei, W., Chen, Z., & Wang, X. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512317 · Cited by 90
Khan, S. H., Choi, Y., Veena, M. S., Lee, J. K., & Shin, D. S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1489827 · Cited by 84
Treg programming and therapeutic reprogramming in cancer
Ayala, M. A. M., Li, Z., & DuPage, M. J. P. (2019) · Immunology · doi:10.1111/imm.13058 · Cited by 75
Wang, Y., Wang, J., Yang, X., Yang, J., Lu, P., Zhao, L., Li, B., Pan, H., Jiang, Z., Shen, X., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.628906 · Cited by 76
“Three CAR T cell therapy products targeting CD19 or CD30 (Tecartus, Kymriah, and Yescarta) have been approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies by the year 2020, which demonstrate the effectiveness and safety of cell products transduced with lentiviral vector (4, 5).”
BackgroundSelf-citationSUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors
López-Cobo, S., Fuentealba, J. R., Gueguen, P., Bonté, P.-E., Tsalkitzi, K., Chacón, I., Glauzy, S., Bohineust, A., Biquand, A., Silva, L., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1350 · Cited by 72
Wiebking, V., Lee, C. M., Mostrel, N., Lahiri, P., Bak, R. O., Bao, G., Roncarolo, M. G., Bertaina, A., & Porteus, M. H. (2020) · Haematologica · doi:10.3324/haematol.2019.233882 · Cited by 73
Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis
Pandey, S. P., Bender, M. J., McPherson, A. C., Phelps, C. M., Sanchez, L. M., Rana, M., Hedden, L., Sangani, K. A., Chen, L., Shapira, J. H., et al. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.05.006 · Cited by 72
The Chimeric Antigen Receptor Detection Toolkit
Hu, Y., & Huang, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01770 · Cited by 71
“This antibody has since been used to characterize CAR-T cells in preclinical studies (16, 24) and clinical trials (50).”
BackgroundMethodGenome-edited allogeneic donor “universal” chimeric antigen receptor T cells
Qasim, W. (2022) · Blood · doi:10.1182/blood.2022016204 · Cited by 70
Modular pooled discovery of synthetic knockin sequences to program durable cell therapies
Blaeschke, F., Chen, Y. Y., Apathy, R., Dániel, B., Chen, A. Y., Chen, P. A., Sándor, K., Zhang, W., Li, Z., Mowery, C. T., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.013 · Cited by 71
Rewriting History: Epigenetic Reprogramming of CD8+ T Cell Differentiation to Enhance Immunotherapy
Zebley, C. C., Gottschalk, S. M., & Youngblood, B. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.06.008 · Cited by 71
“This is probably best exemplified by a recent case report on the vector integration-mediated disruption of the Tet methylcytosine dioxygenase 2 (TET2) gene (encoding an enzyme that regulates DNA demethylation) in CAR T cells; this disruption resulted in clonal expansion of a single CAR T cell that induced leukemia rem…”
BackgroundClonal hematopoiesis and non-hematologic disorders
Jaiswal, S. (2020) · Blood · doi:10.1182/blood.2019000989 · Cited by 182
Toward Better Understanding and Management of CAR-T Cell–Associated Toxicity
Schmidts, A., Wehrli, M., & Maus, M. V. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-061119-015600 · Cited by 69
T Cell Exhaustion and CAR‐T Immunotherapy in Hematological Malignancies
Tang, L., Zhang, Y., Hu, Y., & Mei, H. (2021) · BioMed Research International · doi:10.1155/2021/6616391 · Cited by 72
Shao, M., Teng, X., Guo, X., Zhang, H., Huang, Y., Cui, J., Si, X., Ding, L., Wang, X., Li, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202103508 · Cited by 67
Epigenetic Regulation of T Cell Memory: Recalling Therapeutic Implications
Tough, D. F., Rioja, I., Modis, L. K., & Prinjha, R. K. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.11.008 · Cited by 67
Clonal hematopoiesis as a model for premalignant changes during aging
Steensma, D. P., & Ebert, B. L. (2019) · Experimental Hematology · doi:10.1016/j.exphem.2019.12.001 · Cited by 65
Liu, D., Badeti, S., Dotti, G., Jiang, J.-G., Wang, H., Dermody, J. J., Soteropoulos, P., Streck, D. L., Birge, R. B., & Liu, C. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00617-7 · Cited by 68
“Recent studies reported that CD19CAR vector integration (within the host TET2 gene) was associated with CLL remission and integration-site distributions was linked to treatment outcomes [68, 69].”
BackgroundOxygen regulation of TET enzymes
Matulevičiūtė, R., Cunha, P. P., Johnson, R. S., & Foskolou, I. P. (2021) · FEBS Journal · doi:10.1111/febs.15695 · Cited by 69
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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