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Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. ​

Literature Information ​

DOI10.1056/NEJMoa1103849
PMID21830940
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2011
Times Cited1904
KeywordsChimeric Antigen Receptor, Chronic Lymphocytic Leukemia, T Cells, Immune Response, Cell Therapy
Literature TypeCase Reports, Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages725-33
Issue365(8)
AuthorsDavid L Porter, Bruce L Levine, Michael Kalos, Adam Bagg, Carl H June

TL;DR ​

This study developed a lentiviral vector to create chimeric antigen receptor (CAR) T cells targeting CD19 for treating refractory chronic lymphocytic leukemia (CLL), resulting in over a 1000-fold expansion of the modified T cells and prompting complete remission in a patient. The findings highlight the potential of CAR T-cell therapy in achieving long-lasting remission while monitoring for chronic effects like hypogammaglobulinemia.

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Chimeric Antigen Receptor · Chronic Lymphocytic Leukemia · T Cells · Immune Response · Cell Therapy

Abstract ​

We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.

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Primary Questions Addressed ​

  1. What are the long-term effects of chimeric antigen receptor-modified T cell therapy on patients with chronic lymphocytic leukemia?
  2. How does the persistence of engineered T cells in the bloodstream correlate with the duration of remission in CLL patients?
  3. What alternative costimulatory receptors could enhance the efficacy of chimeric antigen receptor T cells in treating CLL?
  4. How does the development of hypogammaglobulinemia impact the overall health and immune function of patients after CAR T cell therapy?
  5. What are the potential strategies to mitigate the side effects associated with chimeric antigen receptor-modified T cell treatments in CLL?

Key Findings ​

Research Background and Objectives ​

Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow, characterized by the accumulation of abnormal B lymphocytes. Traditional treatments often have limited effectiveness, especially in refractory cases. This study aimed to evaluate the efficacy and safety of a novel lentiviral vector expressing a chimeric antigen receptor (CAR) targeting CD19 in T cells, combined with costimulatory and signaling domains, in patients with refractory CLL.

Main Methods/Materials/Experimental Design ​

The study employed a lentiviral vector to modify T cells from patients, allowing them to express a CAR specific to CD19. The experimental design included the following key steps:

Mermaid diagram
  1. Lentiviral Vector Design: The vector was designed to express a CAR specific for CD19, along with CD137 and CD3-zeta signaling domains.
  2. T Cell Modification: Autologous T cells were modified to express the CAR.
  3. Reinfusion: A low dose (approximately 1.5×10^5 cells/kg) of modified T cells was reinfused into a patient with refractory CLL.
  4. Monitoring: Patient responses were monitored for efficacy and toxicity over time.

Key Results and Findings ​

  • The modified T cells expanded more than 1000-fold from the initial engraftment level in vivo.
  • Complete remission of CLL was observed, with remission lasting for at least 10 months post-treatment.
  • The main toxic effects included tumor lysis syndrome and lymphopenia, with hypogammaglobulinemia as a chronic effect.
  • Engineered T cells persisted in high levels in the blood and bone marrow for up to 6 months, maintaining CAR expression.
  • A specific immune response was detected in the bone marrow, leading to the loss of normal B cells and leukemia cells expressing CD19.

Main Conclusions/Significance/Innovativeness ​

This study demonstrates that CAR T-cell therapy targeting CD19 is a promising treatment for refractory CLL, showing significant expansion, persistence, and clinical efficacy. The results suggest that this approach can lead to complete remission in patients who have exhausted other treatment options. The study also highlights the potential for engineered T cells to maintain long-term activity against cancer cells while outlining the associated toxicities.

Research Limitations and Future Directions ​

  • Limitations: The study involved a single patient, limiting the generalizability of the findings. The long-term effects and safety of this therapy require further investigation in larger cohorts.
  • Future Directions: Future research should focus on:
    • Expanding the patient population to validate efficacy and safety.
    • Investigating the mechanisms underlying the immune response and persistence of CAR T cells.
    • Exploring combination therapies to enhance the effectiveness and reduce toxicities associated with CAR T-cell therapy.

References ​

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Literatures Citing This Work ​

  1. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. - Michael Kalos;Bruce L Levine;David L Porter;Sharyn Katz;Stephan A Grupp;Adam Bagg;Carl H June - Science translational medicine (2011)
  2. Treatment of advanced leukemia in mice with mRNA engineered T cells. - David M Barrett;Yangbing Zhao;Xiaojun Liu;Shuguang Jiang;Carmine Carpenito;Michael Kalos;Richard G Carroll;Carl H June;Stephan A Grupp - Human gene therapy (2011)
  3. Biomarkers in T cell therapy clinical trials. - Michael Kalos - Journal of translational medicine (2011)
  4. Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants. - Karen M Kaluza;Jill M Thompson;Timothy J Kottke;Heather C Flynn Gilmer;Darlene L Knutson;Richard G Vile - International journal of cancer (2012)
  5. Evaluation of current cancer immunotherapy: hemato-oncology. - Christopher S Hourigan;Hyam I Levitsky - Cancer journal (Sudbury, Mass.) (2011)
  6. Gene therapies advance towards finish line. - Asher Mullard - Nature reviews. Drug discovery (2011)
  7. Engineered T-cell therapy shows efficacy in blood cancer. - Simon Frantz - Nature biotechnology (2011)
  8. Science gone translational: the OX40 agonist story. - Andrew D Weinberg;Nicholas P Morris;Magdalena Kovacsovics-Bankowski;Walter J Urba;Brendan D Curti - Immunological reviews (2011)
  9. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. - Padmanee Sharma;Klaus Wagner;Jedd D Wolchok;James P Allison - Nature reviews. Cancer (2011)
  10. Comparison of mRNA and lentiviral based transfection of natural killer cells with chimeric antigen receptors recognizing lymphoid antigens. - Laurent Boissel;Monica Betancur;Weiquan Lu;Winfried S Wels;Teresa Marino;Richard A Van Etten;Hans Klingemann - Leukemia & lymphoma (2012)

... (1894 more literatures)

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