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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].”
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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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ResultCAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn
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“Severe symptoms may require treatment with single agents or combination with dexamethasone (10mg intravenously or orally) (51, 53).”
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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