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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The adverse effects of CAR T-cell therapy appear to be mechanism based and not a result of using viral vectors.
“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]
The Results (Cytokine-Release Syndrome) link a major toxic effect to cytokines associated with T-cell activation, supporting a therapy-related mechanism for that effect. But the Discussion says the mechanism of neurologic toxicity is unknown, and our copy does not establish that adverse effects are unrelated to viral vectors. Page numbers were not available in the indexed passages. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe anti-IL-6R antibodies tocilizumab and sarilumab are used to treat RA, Castleman's disease and CAR-T-induced CRS.
“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]
The Results (Cytokine-Release Syndrome) report that tocilizumab, an IL-6 receptor–blocking antibody, was used to manage severe cytokine-release syndrome after CAR-T therapy. The cited paper does not support the claims about sarilumab or use for rheumatoid arthritis or Castleman’s disease. (LLM, conf=0.88)
Experimental — accuracy not yet measuredClinical 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.
“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]
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.
“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]
The anti-IL-6R antibody tocilizumab is effective at treating patients with CAR-T-induced cytokine release syndrome.
“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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“AIncludes complex karyotype, gain 1q, deletion 17p, t(14;16), and/or t(4;14).”
BackgroundMethodResultInfluentialSelf-citation
- 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 · 2013: 3 · 2012: 4
- 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 › Public Health, Environmental and Occupational Health › 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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