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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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.
“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]
The Methods section ('Patient samples' and 'CAR T-cell manufacturing and correlative studies'; page not available) describes obtaining autologous T cells but does not assess variability in starting-material composition. Searches for patient age, underlying disease, and prior lymphotoxic treatment found no passage linking those factors to that composition. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn that patient, T cells carrying a lentiviral insertion in TET2 expanded preferentially at peak response and probably contributed to the complete response.
“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
A recent case of CAR T cell therapy for CLL illustrated the potential of human primary T cell loss-of-function screens.
“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
There is a report of an exceptional response in a patient with CLL treated by infusion of CAR T-cells in which the CAR construct disrupted one copy of TET2, while the other copy had been previously mutated somatically.
“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 conclusion, the administration of T cells derived from significant clonal expansion of a single CAR-transduced T-cell with biallelic TET2 malfunction converted a non-curative response in a 78-yearold CLL patient into a deep molecular remission.(422) Changes in the epigenetic environment that enhance the efficacy of…”
BackgroundSelf-citationEmerging Cellular Therapies for Cancer
Guedan, S., Ruella, M., & June, C. H. (2018) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041407 · Cited by 386 · see citing works
“Recent work shows that in exceptional conditions, the progeny of a single CAR-T cell is sufficient to mediate potent antitumor effects in advanced leukemia, suggesting that quality of the infused T cells may be more critical than quantity (134).”
BackgroundSelf-citationCAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?
Wagner, J., Wickman, E., DeRenzo, C. C., & Gottschalk, S. M. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.09.015 · Cited by 383 · see citing works
Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy
Gong, Y., Klein Wolterink, R. G. J., Wang, J., Bos, G. M. J., & Germeraad, W. T. V. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01083-5 · Cited by 379 · see citing works
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Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma
Braun, D. A., Bakouny, Z., Hirsch, L., Flippot, R., Van Allen, E. M., Wu, C. J., & Choueiri, T. K. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-00455-z · Cited by 356 · see citing works
Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity
Prinzing, B., Zebley, C. C., Petersen, C. T., Fan, Y., Anido, A. A., Yi, Z., Nguyen, P., Houke, H., Bell, M., Haydar, D., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abh0272 · Cited by 349 · see citing works
Epigenetic modulation of antitumor immunity for improved cancer immunotherapy
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“Perhaps more importantly, disruption of TET2 expression enhances the therapeutic efficacy of adoptively-transferred CD19-targeted CAR-T cells in the setting of hematologic malignancies [36].”
BackgroundT cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance
Chandran, S. S., & Klebanoff, C. A. (2019) · Immunological Reviews · doi:10.1111/imr.12772 · Cited by 325 · see citing works
Epigenetic regulation of T cell exhaustion
Belk, J. A., Dániel, B., & Satpathy, A. T. (2022) · Nature Immunology · doi:10.1038/s41590-022-01224-z · Cited by 334 · see citing works
Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy
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CAR-T cell manufacturing: Major process parameters and next-generation strategies
Ceja, M. A., Khericha, M., Harris, C., Puig-Saus, C., & Chen, Y. (2024) · Journal of Experimental Medicine · doi:10.1084/jem.20230903 · Cited by 293 · see citing works
“…cell therapy appeared to correlate with the expansion of a single CAR-T cell clone whose CAR transgene was randomly inserted in the TET2 locus, thereby knocking out the only functional TET2 copy as the patient had a congenital mis-sense mutation in the other TET2 allele (Fraietta et al., 2018b).”
BackgroundUniversal CARs, universal T cells, and universal CAR T cells
Zhao, J., Lin, Q., Song, Y., & Liu, D. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0677-2 · Cited by 315 · see citing works
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Non-viral precision T cell receptor replacement for personalized cell therapy
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Parallel analysis of transcription, integration, and sequence of single HIV-1 proviruses
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“…(Figures 5 and 6A), which encodes a lysine-specific demethylase that can enhance cell-autonomous proliferation through downregulation of TET2 (Chen et al., 2017b); disruption of TET2 has previously been associated with enhanced clonal proliferation of CAR-encoding T cells (Fraietta et al., 2018).”
BackgroundT cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy
Ghilardi, G., Fraietta, J., Gerson, J., Deerlin, V. V., Morrissette, J. J. D., Caponetti, G. C., Paruzzo, L., Harris, J., Chong, E. A., Susanibar-Adaniya, S., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-02826-w · Cited by 249 · see citing works
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Challenges and new technologies in adoptive cell therapy
Zhang, P., Zhang, G., & Wan, X. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01492-8 · Cited by 271 · see citing works
“Jain N, Zhao Z, Feucht J, Koche R, Iyer A, Dobrin A, et al. TET2 guards against unchecked BATF3-induced CAR T cell expansion.”
BackgroundInfluentialClonal Hematopoiesis–Driver DNMT3A Mutations Alter Immune Cells in Heart Failure
Abplanalp, W. T., Cremer, S., John, D., Hoffmann, J., Schuhmacher, B., Merten, M., Rieger, M. A., Vasa‐Nicotera, M., Zeiher, A. M., & Dimmeler, S. (2020) · Circulation Research · doi:10.1161/circresaha.120.317104 · Cited by 261 · see citing works
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“Geyer MB, et al. Autologous CD19-targeted CAR T cells in patients with residual CLL following initial purine analog-based therapy.”
BackgroundFOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy
Chan, J. D., Scheffler, C. M., Munoz, I., Sek, K., Lee, J. N., Huang, Y., Yap, K. M., Saw, N. Y. L., Li, J., Chen, A. X. Y., et al. (2024) · Nature · doi:10.1038/s41586-024-07242-1 · Cited by 251 · see citing works
Cellular networks controlling T cell persistence in adoptive cell therapy
Chan, J. D., Lai, J., Slaney, C. Y., Kallies, A., Beavis, P. A., & Darcy, P. K. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00539-6 · Cited by 242 · see citing works
The Contribution of Epigenetics to Cancer Immunotherapy
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Stem-like exhausted and memory CD8+ T cells in cancer
Gebhardt, T., Park, S. L., & Parish, I. A. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00615-0 · Cited by 216 · see citing works
“…CAR constructs to the endogenous TCR locus 254 , to limit terminal exhaustion; and the rational knockout or over-expression of transcription factors 255–257 , epigenetic regulators 108,258,259 , engineered cytokine receptors 260,261 and other factors 227,262,263 to enrich stem-like populations.”
BackgroundThe future of engineered immune cell therapies
Irvine, D. J., Maus, M. V., Mooney, D. J., & Wong, W. W. (2022) · Science · doi:10.1126/science.abq6990 · Cited by 213 · see citing works
Sorkhabi, A. D., Khosroshahi, L. M., Sarkesh, A., Mardi, A., Aghebati‐Maleki, A., Maleki, L. A., & Baradaran, B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1113882 · Cited by 215 · see citing works
Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy
Hamilton, M. P., Sugio, T., Noordenbos, T., Shi, S., Bulterys, P. L., Liu, C. L., Kang, X., Olsen, M. N., Good, Z., Dahiya, S., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2401361 · Cited by 220 · see citing works
Chimeric antigen receptor T cell persistence and memory cell formation
McLellan, A. D., & Rad, S. M. A. H. (2019) · Immunology and Cell Biology · doi:10.1111/imcb.12254 · Cited by 209 · see citing works
“The conclusion being that tet2 mutations not only conferred a cell division survival advantage, but also enabled potent anti-tumor activity.(64) T cell suppression by tet2 may be explained by a loss of DNA methylation at the PD-1 promotor region.”
BackgroundInfluentialGene editing for immune cell therapies
Bailey, S. R., & Maus, M. V. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0137-8 · Cited by 202 · see citing works
Ottaviano, G., Georgiadis, C., Gkazi, S. A., Syed, F., Zhan, H., Etuk, A., Preece, R., Chu, J., Kubat, A., Adams, S., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abq3010 · Cited by 175 · see citing works
Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges
Cavazzana, M., Bushman, F. D., Miccio, A., André‐Schmutz, I., & Six, E. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0020-9 · Cited by 198 · see citing works
Self-citationImpact of Manufacturing Procedures on CAR T Cell Functionality
Watanabe, N., Mo, F., & McKenna, M. K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.876339 · Cited by 199 · see citing works
“Blocking BRD4 also leads to upregulation of CAR transgene expression and methylcytosine dioxygenase TET2 gene (73) downregulation, ultimately improving functionality of CAR T cells derived from non-responding CLL patients (72).”
BackgroundThe mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function
Wenes, M., Jaccard, A., Wyss, T., Maldonado‐Pérez, N., Teoh, S. T., Lepez, A., Renaud, F., Franco, F., Waridel, P., Maroun, C. Y., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.03.013 · Cited by 199 · see citing works
“It has been shown that the infusion of T cells with a self-renewing, memory phenotype confers a stronger and more sustained antitumor response (Chen et al., 2021a; Fraietta et al., 2018; Klebanoff et al., 2011).”
BackgroundSleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities
Magnani, C. F., Gaipa, G., Lussana, F., Belotti, D., Gritti, G., Napolitano, S., Matera, G., Cabiati, B., Buracchi, C., Borleri, G., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci138473 · Cited by 193 · see citing works
“As documented in CAR T cell trials using viral vectors, vector insertion within the CBL oncogene and disruption of the normal TET2 allele were reported (56, 57).”
BackgroundEfficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma
Hsiang-Chi, T., Xiong, W., Badeti, S., Yang, Y., Ma, M., Liu, T., Ramos, C. A., Dotti, G., Fritzky, L., Jiang, J.-G., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18444-2 · Cited by 197 · see citing works
CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies
Knochelmann, H. M., Smith, A. S., Dwyer, C. J., Wyatt, M. M., Mehrotra, S., & Paulos, C. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01740 · Cited by 186 · see citing works
“For a patient in complete remission from CLL after CD19-CAR T therapy, CAR integration into the tumor suppressor gene, TET2, resulted in robust clonal proliferation of CAR T cells with a predominantly CM phenotype (112).”
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 188 · see citing works
“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 188 · see citing works
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 199 · see citing works
“…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 198 · see citing works
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 178 · see citing works
“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 182 · see citing works
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 177 · see citing works
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 174 · see citing works
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 184 · see citing works
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 172 · see citing works
“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 175 · see citing works
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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 160 · see citing works
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 160 · see citing works
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 166 · see citing works
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 · see citing works
“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 161 · see citing works
“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 159 · see citing works
“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 159 · see citing works
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 158 · see citing works
“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 156 · see citing works
“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 · see citing works
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 · see citing works
“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 154 · see citing works
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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 · see citing works
Bushman, F. D. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2019.12.009 · Cited by 153 · see citing works
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 150 · see citing works
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 148 · see citing works
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 147 · see citing works
“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 143 · see citing works
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 144 · see citing works
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 144 · see citing works
“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 143 · see citing works
Self-citationStock, S., Schmitt, M. W., & Sellner, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246223 · Cited by 143 · see citing works
“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 143 · see citing works
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 146 · see citing works
“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 141 · see citing works
“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 .”
- 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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