Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia

N Engl J Med. 2014 Oct 16;371(16):1507-17. doi: 10.1056/NEJMoa1407222.

Abstract

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.).

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antigens, CD19*
  • Child
  • Child, Preschool
  • Chimera
  • Cytokines / blood
  • Female
  • Genetic Engineering
  • Genetic Therapy*
  • Genetic Vectors
  • Humans
  • Immunotherapy*
  • Lentivirus / genetics
  • Male
  • Middle Aged
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / mortality
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / therapeutic use*
  • Recurrence
  • Remission Induction
  • Survival Rate
  • T-Lymphocytes / immunology*
  • Young Adult

Substances

  • Antibodies, Monoclonal, Humanized
  • Antigens, CD19
  • Cytokines
  • Receptors, Antigen, T-Cell
  • tocilizumab

Associated data

  • ClinicalTrials.gov/NCT01029366
  • ClinicalTrials.gov/NCT01626495