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Chimeric antigen receptor T cells for sustained remissions in leukemia. ​

Literature Information ​

DOI10.1056/NEJMoa1407222
PMID25317870
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2014
Times Cited2888
KeywordsChimeric Antigen Receptor T Cells, Acute Lymphoblastic Leukemia, Remission Rate
Literature TypeClinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages1507-17
Issue371(16)
AuthorsShannon L Maude, Noelle Frey, Pamela A Shaw, Richard Aplenc, David M Barrett, Nancy J Bunin, Anne Chew, Vanessa E Gonzalez, Zhaohui Zheng, Simon F Lacey, Yolanda D Mahnke, Jan J Melenhorst, Susan R Rheingold, Angela Shen, David T Teachey, Bruce L Levine, Carl H June, David L Porter, Stephan A Grupp

TL;DR ​

This study demonstrates that chimeric antigen receptor-modified T-cell therapy targeting CD19 (CTL019) is highly effective in treating relapsed or refractory acute lymphoblastic leukemia (ALL), achieving a complete remission rate of 90% in a cohort of 30 patients, including those with previous treatment failures. The results highlight the potential of CTL019 to induce durable remissions, with a 6-month event-free survival rate of 67%, suggesting its significant role in improving outcomes for patients with this challenging disease.

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Chimeric Antigen Receptor T Cells · Acute Lymphoblastic Leukemia · Remission Rate

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.).

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Primary Questions Addressed ​

  1. What are the long-term effects of chimeric antigen receptor T cell therapy on patients with relapsed acute lymphoblastic leukemia?
  2. How does the efficacy of CTL019 compare to other treatment options for refractory acute lymphoblastic leukemia?
  3. What specific patient characteristics are associated with a higher risk of severe cytokine-release syndrome following CTL019 infusion?
  4. How does the persistence of CTL019 T cells correlate with the overall survival rates in patients with relapsed ALL?
  5. What are the mechanisms underlying the development of blinatumomab-refractory disease in patients treated with CTL019?

Key Findings ​

Background and Objective ​

Relapsed acute lymphoblastic leukemia (ALL) presents significant treatment challenges, with conventional therapies often proving ineffective. The study investigates the use of chimeric antigen receptor (CAR) T-cell therapy, specifically targeting CD19, as a potential solution to overcome these limitations and induce remission in patients with refractory disease.

Main Methods/Materials/Experimental Design ​

The study involved a clinical trial where autologous T cells were modified with a CD19-directed CAR (CTL019) using a lentiviral vector. The trial included 30 patients (aged 5 to 60 years) with relapsed or refractory ALL. Key aspects of the methodology included:

  1. Leukapheresis: Collection of T cells from patients.
  2. T-cell Activation: T cells were stimulated with paramagnetic beads coated with anti-CD3 and anti-CD28 antibodies.
  3. Transduction: The activated T cells were transduced with the CTL019 vector.
  4. Infusion: Patients received CTL019 cells at varying doses (0.76×10^6 to 20.6×10^6 cells/kg).
  5. Monitoring: Patients were monitored for response rates, toxicity, and the persistence of CTL019 T cells.

The following flowchart summarizes the experimental design:

Mermaid diagram

Key Results and Findings ​

  • Response Rate: 90% (27 out of 30) achieved complete remission after 1 month.
  • Persistence: CTL019 cells were detectable in blood and other tissues, with a 68% probability of persistence at 6 months.
  • Event-Free Survival: 67% at 6 months; Overall survival was 78%.
  • Cytokine-Release Syndrome: All patients experienced this side effect, with 27% suffering severe cases, effectively managed with tocilizumab.
  • B-cell Aplasia: Occurred in all responding patients, indicating effective T-cell activity.

Main Conclusions/Significance/Innovativeness ​

The study concludes that CAR T-cell therapy targeting CD19 (CTL019) is a promising treatment for relapsed and refractory ALL, demonstrating high remission rates and sustained remissions. This approach is particularly innovative as it shows effectiveness even in patients previously unresponsive to other therapies, including stem-cell transplantation and bispecific antibodies like blinatumomab.

Research Limitations and Future Directions ​

  • Limitations: The study was limited by its small sample size and lack of a control group. Long-term effects and the potential for CD19-negative relapses were not fully explored.
  • Future Directions: Further studies are needed to investigate the mechanisms behind relapses, the long-term persistence of CTL019 cells, and the efficacy of combining CTL019 with other therapies, including allogeneic stem-cell transplantation.
AspectDetails
Sample Size30 patients (5-60 years old)
Complete Remission Rate90% (27 patients)
Event-Free Survival67% at 6 months
Overall Survival78% at 6 months
Major Toxic EffectsCytokine-release syndrome (all patients), severe in 27%
Management of ToxicityTocilizumab used effectively for severe cases
B-cell AplasiaObserved in all responders, lasting up to 1 year

This study significantly contributes to the field of hematology and oncology by demonstrating the potential of CAR T-cell therapy in a challenging patient population, setting the stage for future research and clinical applications.

References ​

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  2. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. - David L Porter;Bruce L Levine;Michael Kalos;Adam Bagg;Carl H June - The New England journal of medicine (2011)
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Literatures Citing This Work ​

  1. Toward synthetic biology with engineered T cells: a long journey just begun. - Carl H June - Human gene therapy (2014)
  2. Immunotherapy: CAR-modified T cells targeting CD19-curing the incurable. - Lisa Hutchinson - Nature reviews. Clinical oncology (2014)
  3. Immune-based therapies for childhood cancer. - Crystal L Mackall;Melinda S Merchant;Terry J Fry - Nature reviews. Clinical oncology (2014)
  4. Central nervous system involvement in adult acute lymphoblastic leukemia: diagnostic tools, prophylaxis, and therapy. - Maria Ilaria Del Principe;Luca Maurillo;Francesco Buccisano;Giuseppe Sconocchia;Mariagiovanna Cefalo;Giovanna De Santis;Ambra Di Veroli;Concetta Ditto;Daniela Nasso;Massimiliano Postorino;Marco Refrigeri;Cristina Attrotto;Giovanni Del Poeta;Francesco Lo-Coco;Sergio Amadori;Adriano Venditti - Mediterranean journal of hematology and infectious diseases (2014)
  5. T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. - Cor H J Lamers;Sabine van Steenbergen-Langeveld;Mandy van Brakel;Corrien M Groot-van Ruijven;Pascal M M L van Elzakker;Brigitte van Krimpen;Stefan Sleijfer;Reno Debets - Human gene therapy methods (2014)
  6. Advances in T-cell therapy for ALL. - Stephan A Grupp - Best practice & research. Clinical haematology (2014)
  7. Developers seek to finetune toxicity of T-cell therapies. - Chris Morrison - Nature biotechnology (2014)
  8. When cancer and immunology meet. - Martin Carroll - Immunological reviews (2015)
  9. Modern immunotherapy of adult B-lineage acute lymphoblastic leukemia with monoclonal antibodies and chimeric antigen receptor modified T cells. - Elena Maino;Anna Maria Scattolin;Piera Viero;Rosaria Sancetta;Anna Pascarella;Michele Vespignani;Renato Bassan - Mediterranean journal of hematology and infectious diseases (2015)
  10. Treatment strategies in patients with AML or high-risk myelodysplastic syndrome relapsed after Allo-SCT. - T Sauer;G Silling;C Groth;F Rosenow;U Krug;D Görlich;G Evers;J Albring;R Besoke;R M Mesters;C Müller-Tidow;T Kessler;T Büchner;W E Berdel;M Stelljes - Bone marrow transplantation (2015)

... (2878 more literatures)

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