Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia

By S. Maude, N. Frey, Pamela A. Shaw, R. Aplenc, D. Barrett, N. Bunin, A. Chew, V. Gonzalez, Zhaohui Zheng, S. Lacey and 9 more. New England Journal of Medicine, 2014

4,883 citations recorded by the source corpus.

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 0.76×106 to 20.6×106 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.)

Subfields: Genetics, Oncology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/921865bc45e5623e994a1cf872b524bcbb38bc81

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

In Oncology

In Public Health, Environmental and Occupational Health

James J. Collins

Citations in the corpus

ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells (2018, background): “Hemophagocytic lymphohistiocytosis or macrophage activation syndrome (HLH/MAS) overlaps substantially with CRS, as illustrated by ferritin elevations seen in many CAR T cell recipients during CRS [2,12,20,22,27].”
Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo (2015, positive): “Impressive responses have been achieved in some patients with refractory acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin’s lymphoma after infusing autologous T-cells expressing a CAR specific for the B-lineage molecule CD19 3–8 .”
Gene therapy comes of age (2018, positive): “CAR-T cells have had a large impact on the treatment of certain cancers (139), and this success provides a foundation for future T cell–based therapies for other cancers and other diseases such as autoimmune disorders and AIDS (5, 140).”
Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia (2016, methodology): “Data on response to CTL019 in the first 30 patients (25 children and 5 adults) were recently published, demonstrating a 90% CR rate and a 6-month event-free survival (EFS) rate of 67% (2).”
CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL (2017, neutral): “13 However, the likelihood of durable remission following CD19 targeted immunotherapy remains unknown.”
Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses (2018, positive): “As many patients treated with CAR T cell therapy face cytokine release syndrome, which can be life threatening (Maude et al., 2014b; Morgan et al., 2010), it is important to prevent CAR T cell activity when necessary.”
Gene therapy clinical trials worldwide to 2017: An update (2018, background): “Since the 2011 report in the New England Journal of Medicine that described one patient who went into complete remission following an infusion of transduced autologous T cells, modified to express a CAR with specificity for the B‐cell antigen CD19,(19) there have been hundreds of patients treated in”
Cytokine release syndrome (2018, background): “In pediatric patients with ALL the incidence of CRS following infusion of CD19targeted CAR T cells was 30/30 (100%) and 16/21 (76%) in two clinical trials testing distinct 19-targeted CAR constructs [39, 41].”