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Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Open accessAbstract
BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. METHODS: We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. RESULTS: A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. CONCLUSIONS: Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).
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“however, as with TCRs, the adverse effects of CAR T-cell therapy appear to be mechanism based and not a result of using viral vectors [74].”
From Clinical use of lentiviral vectors (2018) · cites this paper as [74]
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“The anti-IL-6R antibodies tocilizumab and sarilumab are used to treat RA, Castleman’s disease and CAR-T-induced CRS (71–75, 352, 364) and have promise for treating the severe form of COVID-19 (365–367).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [364]
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“Clinical trials using CD19-targeted CAR T-cell therapy for B-cell acute lymphoblastic leukemia have demonstrated high efficacy, with durable complete response rates in >60% of patients with relapsed or refractory disease [74, 75].”
From Clinical use of lentiviral vectors (2018) · cites this paper as [74]
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“One important on-target side effect of CD19 CAR T-cell therapy is B-cell aplasia, which is associated with long-term CAR T-cell persistence [74].”
From Clinical use of lentiviral vectors (2018) · cites this paper as [74]
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“The anti-IL-6R antibody tocilizumab is effective at treating patients with CAR-T-induced cytokine release syndrome (CRS) (352, 364) and is being considered for treating ARDS in COVID-19 patients (365–368).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [364]
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“In patients who received tocilizumab, severe clinical manifestations rapidly improved 1–3 days after injection (Maude et al., 2014”
From Targeting Interleukin-6 Signaling in Clinic (2019) · cites this paper as Maude et al., 2014
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Nano-optogenetic engineering of CAR T cells for precision immunotherapy with enhanced safety
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“A dramatic elevation of IL-6 is one of the critical hallmarks of CRS, along with elevated granulocyte macrophage colony-stimulating factor (GMCSF), IFN-γ and IL-10 23,24 .”
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“CD8α-HD/TMD shares 62.8% AA identity between mice and humans, whereas CD28-HD/TMD shares 66.8% AA identity (Figure 1C).”
BackgroundInfluentialMiller, J. S., Morishima, C., McNeel, D. G., Patel, M. R., Kohrt, H. E. K., Thompson, J. A., Sondel, P. M., Wakelee, H. A., Disis, M. L., Kaiser, J. C., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2451 · Cited by 203
Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges
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Various Aspects of a Gene Editing System—CRISPR–Cas9
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“Therapy using CAR-T cells against CD19 was effective for treatment of ALL and was related to a high remission rate also in patients for whom stem-cell transplantation was unsuccessful [99].”
Garfall, A. L., Stadtmauer, E. A., Hwang, W., Lacey, S. F., Melenhorst, J. J., Krevvata, M., Carroll, M. P., Matsui, W. H., Wang, Q., Dhodapkar, M. V., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.120505 · Cited by 197
Self-citationSleeping 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 201
“While it has been clearly demonstrated that tumor burden is an important factor contributing to CAR T cell expansion, the impact of the infused cell dose remains controversial (7, 49).”
BackgroundChen, F., Teachey, D. T., Pequignot, E. C., Frey, N. V., Porter, D., Maude, S. L., Grupp, S. A., June, C. H., Melenhorst, J. J., & Lacey, S. F. (2016) · Journal of Immunological Methods · doi:10.1016/j.jim.2016.03.005 · Cited by 197
Self-citationTarget selection for CAR-T therapy
Wei, J., Han, X., Bo, J., & Han, W. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0758-x · Cited by 201
Autologous CD33-CAR-T cells for treatment of relapsed/refractory acute myelogenous leukemia
Tambaro, F. P., Singh, H., Jones, E., Rytting, M., Mahadeo, K. M., Thompson, P. A., Daver, N. G., Dinardo, C. D., Kadia, T. M., Garcia‐Manero, G., et al. (2021) · Leukemia · doi:10.1038/s41375-021-01232-2 · Cited by 196
“Remarkable results were achieved with CAR-modified T cells targeting CD19 in relapsed/refractory patients with diffuse large B cell lymphoma (DLBCL) [5] and pediatric B cell acute lymphoblastic leukemia (ALL) [6] (50–90% CR), which inspired development of CAR-T cellular therapy for other indications, such as AML.”
ResultAntigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells
Singh, N., Frey, N. V., Engels, B., Barrett, D. M., Shestova, O. E., Ravikumar, P., Cummins, K. D., Lee, Y. G., Pajarillo, R., Chun, I., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01326-5 · Cited by 199
Self-citationHLA-independent T cell receptors for targeting tumors with low antigen density
Mansilla-Soto, J., Eyquem, J., Haubner, S., Hamieh, M., Feucht, J., Paillon, N., Zucchetti, A. E., Li, Z., Sjöstrand, M., Lindenbergh, P. L., et al. (2022) · Nature Medicine · doi:10.1038/s41591-021-01621-1 · Cited by 190
Cell-based therapy technology classifications and translational challenges
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A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy
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Scarfò, I., & Maus, M. V. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0230-9 · Cited by 195
van Bruggen, J. A. C., Martens, A. W. J., Fraietta, J. A., Hofland, T., Tonino, S. H., Eldering, E., Levin, M.-D., Siska, P. J., Endstra, S., Rathmell, J. C., et al. (2019) · Blood · doi:10.1182/blood.2018885863 · Cited by 187
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Self-citationCAR T-Cell Associated Neurotoxicity: Mechanisms, Clinicopathologic Correlates, and Future Directions
Hunter, B. D., & Jacobson, C. A. (2019) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djz017 · Cited by 200
Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy
Gust, J., Finney, O. C., Li, D., Brakke, H., Hicks, R. M., Futrell, R. B., Gamble, D. N., Rawlings-Rhea, S. D., Khalatbari, H. K., Ishak, G. E., et al. (2019) · Annals of Neurology · doi:10.1002/ana.25502 · Cited by 199
Xu, X. Y., Huang, W. C., Heczey, A. A., Liu, D., Guo, L., Wood, M. S., Jin, J., Courtney, A. N., Liu, B., Pierro, E. J. D., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0421 · Cited by 200
Myers, R. M., Li, Y., Leahy, A. B., Barrett, D. M., Teachey, D. T., Callahan, C. A., Fasano, C., Rheingold, S. R., DiNofia, A. M., Wray, L., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.20.03458 · Cited by 194
“03), categorized as follows: (1) encephalopathy: encephalopathy, depressed level of consciousness, lethargy, somnolence, memory impairment, confusion, delirium, agitation, irritability, hallucinations, altered mood, or mental status change; (2) speech impairment: aphasia, dysphasia, dysarthria, or word-finding difficu…”
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Delivery and Specificity of CRISPR/Cas9 Genome Editing Technologies for Human Gene Therapy
Gori, J. L., Hsu, P. D., Maeder, M. L., Shen, S., Welstead, G. G., & Bumcrot, D. A. (2015) · Human Gene Therapy · doi:10.1089/hum.2015.074 · Cited by 200
Immunogenomic Landscape of Hematological Malignancies
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Current updates on generations, approvals, and clinical trials of CAR T-cell therapy
Dejenie, T. A., Medhin, M. T. G., Terefe, G. D., Admasu, F. T., Tesega, W. W., & Abebe, E. C. (2022) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2022.2114254 · Cited by 210
“nancies, showing that combination therapy is more efficacious than CAR T-cell therapy alone.(118,183,186,187) Despite these early promising results, many more clinical trials on various CAR T-cell-based combination therapies are still in progress to”
BackgroundThe immunopeptidomic landscape of ovarian carcinomas
Schuster, H., Peper-Gabriel, J. K., Bösmüller, H.-C., Roehle, K., Backert, L., Bilich, T., Ney, B., Loeffler, M. W., Kowalewski, D. J., Trautwein, N., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1707658114 · Cited by 188
Drent, E., Poels, R., Ruiter, R. W. J., van de Donk, N. W. C. J., Zweegman, S., Yuan, H., de Bruijn, J. D., Sadelain, M., Lokhorst, H. M., Groen, R. W. J., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2559 · Cited by 195
“In some cases, the expression of the target on healthy tissues can be tolerable and clinicallymanageable, such as the B-cell aplasia caused by CD19 CAR-T cells (4, 9), but in cases where vital tissues are involvedoff-tumor toxicity canbe fatal (10– 12).”
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Self-citationCAR models: next-generation CAR modifications for enhanced T-cell function
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CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies
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Making CAR T Cells a Solid Option for Solid Tumors
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B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
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“CD19targeting CAR-T cells are FDA-approved for the treatment of refractory/relapsed B-cell malignancies [8,9].”
Background
Metadata
- Authors
- Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., Mahnke, Y. D., Melenhorst, J. J., Rheingold, S. R., Shen, A., Teachey, D. T., Levine, B. L., June, C. H., Porter, D. L., & Grupp, S. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Abramson Cancer Center (US)
- University of Pennsylvania (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-10-16
- Volume
- 371
- Issue
- 16
- Pages
- 1507-1517
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4267531
- OpenAlex
- W2118796952
- Cited by
- 5,413
- References
- 30
- Citations by year
- 2026: 228 · 2025: 318 · 2024: 378 · 2023: 505 · 2022: 495 · 2021: 558 · 2020: 665 · 2019: 538 · 2018: 501 · 2017: 541 · 2016: 385 · 2015: 261 · 2014: 24
- FWCI
- 195.01
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-03-10)
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Children's Hospital of Philadelphia
- St. Jude Children's Research Hospital
- School of Medicine, Indiana University
- National Cancer Institute (P30CA147859, R01CA165206, R01CA102646, R01CA116660, T32CA009615, P30CA016520)
- National Institute of Allergy and Infectious Diseases (P30AI045008)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- chimeric antigen receptor T cells, CD19, acute lymphoblastic leukemia, relapsed/refractory leukemia, CAR T-cell therapy, tisagenlecleucel, lentiviral vectors, complete remission, cytokine release syndrome, tocilizumab, B-cell aplasia, stem cell transplantation, event-free survival, sustained remission, pediatric and adult patients
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Chimera, Female, Genetic Engineering, Genetic Vectors, Humans, Immunotherapy, Male, Middle Aged, Receptors, Antigen, T-Cell, Recurrence, Remission Induction, T-Lymphocytes, Genetic Therapy, Survival Rate, Lentivirus, Cytokines, Antigens, CD19, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Young Adult, Antibodies, Monoclonal, Humanized
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