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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
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“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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BackgroundMaking CAR T Cells a Solid Option for Solid Tumors
Schmidts, A., & Maus, M. V. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02593 · Cited by 193
“Further analysis revealed that random insertion of the CAR into the TET2 gene locus had led to disruption of TET2 protein expression in this patient who also had a hypomorphic mutation on their other TET2 allele; the biallelic disruption of TET2 resulted in a central memory state of the T cell clone (65).”
BackgroundCAR T cell therapy: inroads to response and resistance
Brown, C. E., & Mackall, C. L. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-018-0119-y · Cited by 187
Successes and challenges in clinical gene therapy
Kohn, D. B., Chen, Y. Y., & Spencer, M. J. (2023) · Gene Therapy · doi:10.1038/s41434-023-00390-5 · Cited by 209
“…ef fi cacy was attributed in large part to clonal expansion of a particular CAR-T cell that lacked any functional copy of TET2 (the patient had a congenital mutation in one copy of TET2, and the CAR transgene was randomly inserted into the other copy, thereby generating a double-knockout) [77].”
BackgroundFrom concept to cure: The evolution of CAR-T cell therapy
Patel, K. K., Tariveranmoshabad, M., Kadu, S., Shobaki, N., & June, C. H. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.03.005 · Cited by 211
Self-citationLimitations in the Design of Chimeric Antigen Receptors for Cancer Therapy
Stoiber, S., Cadilha, B. L., Benmebarek, M.-R., Lesch, S., Endres, S., & Kobold, S. (2019) · Cells · doi:10.3390/cells8050472 · Cited by 182
“This was illustrated by a report from Fraietta and colleagues, who demonstrated that the progeny of a single CAR T cell clone displayed massive in vivo expansion and consequently led to complete remission of CLL in a 78-year-old patient, who had previously undergone CAR T cell therapy without success [138].”
MethodNext-Generation CAR T-cell Therapies
Young, R. M., Engel, N. W., Uslu, U., Wellhausen, N., & June, C. H. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1683 · Cited by 191
Self-citationHallmarks of the aging T‐cell system
Zhang, H., Weyand, C. M., & Goronzy, J. J. (2021) · FEBS Journal · doi:10.1111/febs.15770 · Cited by 181
Hegde, M. G., Joseph, S. K., Pashankar, F., DeRenzo, C. C., Sanber, K. S., Navai, S. A., Byrd, T. T., Hicks, J. M., Xu, M. L., Gerken, C. P., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17175-8 · Cited by 175
The Epigenetic Hallmarks of Cancer
Esteller, M., Dawson, M. A., Kadoch, C., Rassool, F. V., Jones, P. A., & Baylin, S. B. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0296 · Cited by 202
Allogeneic CAR-T Cells: More than Ease of Access?
Graham, C., Jóźwik, A., Pepper, A. G. S., & Benjamin, R. (2018) · Cells · doi:10.3390/cells7100155 · Cited by 178
“This resulted in a proliferation and survival advantage of CAR-T cells with this disruption as compared to those without [40].”
Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls
Heidarzadeh, M., Özdemir, Y., Kaya, M., Abriz, A. E., Zarebkohan, A., Rahbarghazi, R., & Sokullu, E. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00650-0 · Cited by 183
Minagawa, A., Yoshikawa, T., Yasukawa, M., Hotta, A., Kunitomo, M., Iriguchi, S., Takiguchi, M., Kassai, Y., Imai, E., Yasui, Y., et al. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.10.005 · Cited by 164
Antigen-driven clonal selection shapes the persistence of HIV-1–infected CD4+ T cells in vivo
Simonetti, F. R., Zhang, H., Soroosh, G., Duan, J., Rhodehouse, K., Hill, A. L., Beg, S. A., McCormick, K., Raymond, H. E., Nobles, C. L., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci145254 · Cited by 166
Self-citationLi, W., Qiu, S., Chen, J., Jiang, S., Chen, W., Jiang, J., Wang, F., Si, W., Shu, Y., Wei, P., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.07.011 · Cited by 167
Genetic engineering of T cells for immunotherapy
Ellis, G. I., Sheppard, N. C., & Riley, J. L. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00329-9 · Cited by 170
Clonal haematopoiesis and dysregulation of the immune system
Belizaire, R., Wong, W. J., Robinette, M. L., & Ebert, B. L. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00843-3 · Cited by 161
“Lentiviral integration-mediated disruption of loci encoding genes mutated in CH has also been associated with cell-intrinsic alterations in CAR T cell expansion and differentiation 183–185 .”
Shah, N. N., Qin, H., Yates, B., Su, L., Shalabi, H., Raffeld, M. A., Ahlman, M. A., Stetler‐Stevenson, M., Yuan, C. M., Guo, S., et al. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019000219 · Cited by 162
“Reexpansion of CAR T cells from the original infusion following the contraction phase, to a level exceeding the initial peak, is highly unusual, as is a clonal expansion.(8) We report on a delayed clonal expansion in a patient receiving lentiviral vector-mediated, anti-CD22 CAR T-cell therapy to treat ALL.”
BackgroundInfluentialThe Past, Present, and Future of Non-Viral CAR T Cells
Moretti, A., Ponzo, M., Nicolette, C. A., Tcherepanova, I. Y., Biondi, A., & Magnani, C. F. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.867013 · Cited by 167
“No T cell transformation has been observed even in cases of gammaretroviral vector insertion into an oncogene, such as Cbl, and destruction of a tumor suppressor gene such as Tet Methylcytosine dioxygenase 2 (TET2) by lentiviral vector integration, as has been reported in patients treated with anti-CD19 and anti-CD22…”
BackgroundLi, D., Li, N., Zhang, Y., Fu, H., Feng, M., Schneider, D., Su, L., Wu, X., Zhou, J., Mackay, S., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.02.011 · Cited by 160
T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome
Klebanoff, C. A., Chandran, S. S., Baker, B. M., Quezada, S. A., & Ribas, A. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00809-z · Cited by 164
“Additionally, viruses are expensive to manufacture 51 , can cause insertional mutagenesis 52,53 and possess a relatively limited cargo capacity.”
BackgroundHuang, H., Zhou, P., Wei, J., Long, L., Shi, H., Dhungana, Y., Chapman, N. M., Fu, G., Saravia, J., Raynor, J. L., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.021 · Cited by 157
“Conversely, deficiency of known negative regulators for TMEM formation, including Tet2 (Carty et al., 2018; Fraietta et al., 2018), Acaca (Endo et al.”
BackgroundSelf-citationElsallab, M., Ellithi, M., Lunning, M. A., D'Angelo, C. R., Ma, J., Perales, M., Frigault, M. J., & Maus, M. V. (2024) · Blood · doi:10.1182/blood.2024024166 · Cited by 157
Understanding the mechanisms of resistance to CAR T-cell therapy in malignancies.
Cheng, J., Zhao, L., Zhang, Y., Qin, Y., Guan, Y., Zhang, T., Liu, C., & Zhou, J. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01237 · Cited by 153
“Interestingly, biallelic inactivation of the gene Tet methylcytosine dioxygenase 2 (TET2) improves the persistence of CAR T cells, indicating the importance for identifying genes that determine the persistence of CAR T cells for the long-term prognosis in response to CAR T-cell therapy (79).”
BackgroundTET2 guards against unchecked BATF3-induced CAR T cell expansion
Jain, N., Zhao, Z., Feucht, J., Koche, R. P., Iyer, A., Dobrin, A., Mansilla‐Soto, J., Yang, J. L., Zhan, Y. A., Lopez, M. A., et al. (2023) · Nature · doi:10.1038/s41586-022-05692-z · Cited by 159
Biasco, L., Izotova, N., Rivat, C., Ghorashian, S., Richardson, R., Guvenel, A., Hough, R. E., Wynn, R. F., Popova, B., Lopes, A., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00207-7 · Cited by 155
Cytokine and Chemokine Signals of T‐Cell Exclusion in Tumors
Zhang, Y., Guan, X.-Y., & Jiang, P. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.594609 · Cited by 133
Bushman, F. D. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2019.12.009 · Cited by 160
Self-citationMetabolic challenges and interventions in CAR T cell therapy
Peng, J.-J., Wang, L., Li, Z., Ku, C., & Ho, P. (2023) · Science Immunology · doi:10.1126/sciimmunol.abq3016 · Cited by 156
Ramachandran, I., Lowther, D. E., Dryer-Minnerly, R., Wang, R., Fayngerts, S., Nunez, D., Betts, G. J., Bath, N. M., Tipping, A. J., Melchiori, L., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0762-2 · Cited by 151
Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma
Bedoya, D. M., Dutoit, V., & Migliorini, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.640082 · Cited by 151
“However, it also increases the risk of off-target cleavage that could potentially lead to an excessive proliferation of CAR T cells due to disruption of tumor suppressor genes (79, 80).”
BackgroundClinical investigation of CAR T cells for solid tumors: Lessons learned and future directions
Bagley, S. J., & O’Rourke, D. M. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107419 · Cited by 147
Cancer immunotherapy comes of age and looks for maturity
Finck, A., Gill, S. I., & June, C. H. (2020) · Nature Communications · doi:10.1038/s41467-020-17140-5 · Cited by 143
Self-citationLiu, H., Lei, W., Zhang, C., Yang, C., Wei, J., Guo, Q., Guo, X., Chen, Z., Lu, Y., Young, K. H., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-1457 · Cited by 147
“Upregulation of NKG2D and CD27, a costimulatory receptor involved in the generation of T-cell memory, may contribute to the enhanced cytolytic capacity of CAR T cells (27, 28).”
BackgroundThe model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma
Wei, J., Liu, Y., Wang, C., Zhang, Y., Tong, C., Dai, G., Wang, W., Rasko, J. E. J., Melenhorst, J. J., Qian, W., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00256-x · Cited by 146
Self-citationStock, S., Schmitt, M. W., & Sellner, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246223 · Cited by 146
“These TET2-disrupted CART cells showed a modified T cell differentiation leading to a central memory phenotype at the maximum of proliferation [65].”
BackgroundEngineering-enhanced CAR T cells for improved cancer therapy
Milone, M. C., Xu, J., Chen, S., Collins, M. A., Zhou, J., Powell, D. J., & Melenhorst, J. J. (2021) · Nature Cancer · doi:10.1038/s43018-021-00241-5 · Cited by 148
Self-citationRecent advances and applications of CRISPR-Cas9 in cancer immunotherapy
Liu, Z., Shi, M., Ren, Y., Xu, H., Weng, S., Ning, W., Ge, X., Liu, L., Guo, C., Duo, M., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01738-6 · Cited by 160
“Lentiviral vector-mediated CAR transgene insertion disrupts the gene encoding the methylcytosine dioxygenase TET2 [91], producing powerful CAR-T cells with short-lived memory cell characteristics, which can expand effector cell responses and show the central memory phenotype (CD62L+ cells) associated with higher antit…”
BackgroundInfluentialIn vivo CAR engineering for immunotherapy
Li, Y.-R., Zhu, Y., Halladay, T., & Yang, L. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-025-01174-1 · Cited by 151
“This risk was highlighted in a clinical trial for chronic lymphocytic leukaemia, in which the integration of the CAR construct disrupted the TET2 gene in a CD19-targeting CAR-T cell product, leading to the unexpected hyperproliferation of TET2 -disrupted CAR-T cells 115 .”
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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