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Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. ​

Literature Information ​

DOI10.1056/NEJMoa1215134
PMID23527958
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2013
Times Cited1855
KeywordsChimeric Antigen Receptor, Acute Lymphoblastic Leukemia, Cytokine Release Syndrome
Literature TypeCase Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages1509-1518
Issue368(16)
AuthorsStephan A Grupp, Michael Kalos, David Barrett, Richard Aplenc, David L Porter, Susan R Rheingold, David T Teachey, Anne Chew, Bernd Hauck, J Fraser Wright, Michael C Milone, Bruce L Levine, Carl H June

TL;DR ​

This study investigates the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 in two children with relapsed and refractory pre-B-cell acute lymphoblastic leukemia (ALL), demonstrating significant T cell expansion and complete remission in one patient lasting 11 months, although a relapse occurred in the other due to CD19-negative cells. The findings highlight the potential of CAR T cell therapy in treating aggressive ALL but also underscore the necessity of targeting additional antigens beyond CD19 to address relapses effectively.

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Chimeric Antigen Receptor · Acute Lymphoblastic Leukemia · Cytokine Release Syndrome

Abstract ​

Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.

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Primary Questions Addressed ​

  1. What are the potential alternative targets for chimeric antigen receptor T cells in treating acute lymphoblastic leukemia beyond CD19?
  2. How does the efficacy of chimeric antigen receptor-modified T cells in acute lymphoblastic leukemia compare to their use in chronic lymphocytic leukemia?
  3. What are the long-term outcomes and survival rates for patients treated with chimeric antigen receptor T cells for acute lymphoblastic leukemia?
  4. How can the risk of adverse events, such as cytokine-release syndrome and B-cell aplasia, be mitigated in patients receiving chimeric antigen receptor T cell therapy?
  5. What are the mechanisms behind the loss of CD19 expression in relapsed acute lymphoblastic leukemia, and how can this impact future treatment strategies?

Key Findings ​

Research Background and Purpose ​

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in treating chronic lymphocytic leukemia (CLL), but its effectiveness in acute lymphoblastic leukemia (ALL) remains uncertain. This study aimed to evaluate the safety and efficacy of CAR T-cells targeting CD19 (CTL019) in children with relapsed and refractory pre-B-cell ALL.

Main Methods/Materials/Experimental Design ​

The study involved two pediatric patients diagnosed with relapsed and refractory ALL. They received infusions of CTL019 T-cells, which were generated by transducing peripheral blood mononuclear cells (PBMCs) with a lentiviral vector carrying an anti-CD19 chimeric antigen receptor.

Experimental Design Overview ​

Mermaid diagram
  1. Patient Selection: Two children with relapsed, refractory ALL.
  2. PBMC Collection: Mononuclear cells were collected prior to intensive chemotherapy.
  3. T-cell Transduction: Cells were transduced with a lentiviral vector to express CTL019.
  4. CTL019 Cell Expansion: Cells were expanded using anti-CD3 and anti-CD28 antibodies.
  5. Infusion of CTL019 Cells: Infused at doses ranging from 1.4×10^6 to 1.2×10^7 cells/kg.
  6. Monitoring and Assessment: Patients were monitored for cytokine levels, T-cell expansion, and adverse events.
  7. Data Analysis: Clinical outcomes, including remission status and adverse effects, were analyzed.

Key Results and Findings ​

  • Expansion of CTL019 T-cells: Both patients showed a significant expansion of CTL019 cells in the bloodstream and bone marrow, exceeding 1000-fold from baseline levels.
  • Clinical Outcomes: Complete remission was achieved in both patients, with one maintaining remission for 11 months. The second patient experienced a relapse due to the emergence of CD19-negative leukemic cells.
  • Adverse Events: Both patients experienced grade 3 or 4 adverse events, including cytokine-release syndrome and B-cell aplasia. One patient required treatment with etanercept and tocilizumab for severe cytokine-release syndrome.

Main Conclusions/Significance/Innovation ​

The study provides strong evidence that CAR T-cells targeting CD19 can induce remission in children with relapsed ALL. However, the emergence of CD19-negative blasts in one patient highlights the need for targeting additional antigens. The findings suggest the potential for CAR T-cell therapy as a viable treatment option for high-risk pediatric leukemia, particularly in cases resistant to conventional therapies.

Research Limitations and Future Directions ​

  • Limitations: The study involved only two patients, limiting the generalizability of the results. The long-term safety and efficacy of CAR T-cell therapy in this population remain to be established.
  • Future Directions: Further studies are needed to explore the effectiveness of targeting additional antigens alongside CD19 to prevent relapse. Additionally, larger clinical trials should assess the long-term outcomes and potential adverse effects of CAR T-cell therapy in pediatric ALL.

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)
  3. 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)
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Literatures Citing This Work ​

  1. Zoom Zoom: racing CARs for multiple myeloma. - Marcela V Maus;Carl H June - Clinical cancer research : an official journal of the American Association for Cancer Research (2013)
  2. Advanced targeted, cell and gene-therapy approaches for pediatric hematological malignancies: results and future perspectives. - Chiara F Magnani;Sarah Tettamanti;Francesca Maltese;Nice Turazzi;Andrea Biondi;Ettore Biagi - Frontiers in oncology (2013)
  3. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. - David T Teachey;Susan R Rheingold;Shannon L Maude;Gerhard Zugmaier;David M Barrett;Alix E Seif;Kim E Nichols;Erica K Suppa;Michael Kalos;Robert A Berg;Julie C Fitzgerald;Richard Aplenc;Lia Gore;Stephan A Grupp - Blood (2013)
  4. Young T Cells Age During a Redirected Anti-Tumor Attack: Chimeric Antigen Receptor-Provided Dual Costimulation is Half the Battle. - Andreas A Hombach;Hinrich Abken - Frontiers in immunology (2013)
  5. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. - Gerald P Linette;Edward A Stadtmauer;Marcela V Maus;Aaron P Rapoport;Bruce L Levine;Lyndsey Emery;Leslie Litzky;Adam Bagg;Beatriz M Carreno;Patrick J Cimino;Gwendolyn K Binder-Scholl;Dominic P Smethurst;Andrew B Gerry;Nick J Pumphrey;Alan D Bennett;Joanna E Brewer;Joseph Dukes;Jane Harper;Helen K Tayton-Martin;Bent K Jakobsen;Namir J Hassan;Michael Kalos;Carl H June - Blood (2013)
  6. Cellular immunotherapy for refractory hematological malignancies. - John L Reagan;Loren D Fast;Howard Safran;Martha Nevola;Eric S Winer;Jorge J Castillo;James N Butera;Matthew I Quesenberry;Carolyn T Young;Peter J Quesenberry - Journal of translational medicine (2013)
  7. Perspective: assembly line immunotherapy. - Bruce L Levine;Carl H June - Nature (2013)
  8. Evolutionary dynamics of cancer in response to targeted combination therapy. - Ivana Bozic;Johannes G Reiter;Benjamin Allen;Tibor Antal;Krishnendu Chatterjee;Preya Shah;Yo Sup Moon;Amin Yaqubie;Nicole Kelly;Dung T Le;Evan J Lipson;Paul B Chapman;Luis A Diaz;Bert Vogelstein;Martin A Nowak - eLife (2013)
  9. Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges. - Ethan Q Han;Xiu-ling Li;Chun-rong Wang;Tian-fang Li;Shuang-yin Han - Journal of hematology & oncology (2013)
  10. Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia--implications for immunotherapy. - Gerrit Weber;Ignazio Caruana;Rayne H Rouce;A John Barrett;Ulrike Gerdemann;Ann M Leen;Karen R Rabin;Catherine M Bollard - Clinical cancer research : an official journal of the American Association for Cancer Research (2013)

... (1845 more literatures)

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