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Cited by 2,898CAR-T cell therapy researchAcute Lymphoblastic Leukemia researchImmunotherapy and Immune Responses

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial

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Lee, Daniel W, Kochenderfer, James N, Stetler-Stevenson, Maryalice, Cui, Yongzhi K, Delbrook, Cindy, Feldman, Steven A, Fry, Terry J, Orentas, Rimas +11 more·2015·The Lancet
DOI 10.1016/s0140-6736(14)61403-3PMC PMC7065359
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Abstract

Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. Funding National Institutes of Health Intramural funds and St Baldrick's Foundation.

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  • All approved CAR T-cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) co-stimulatory signals.

    “All approved CAR T-cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) co-stimulatory signals, which are essential for eliciting effector and memory cell expansion and persistence and a clinically relevant immune response (9-15).”

    From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [14]

    The Methods describe a trial CAR incorporating a CD28 signalling domain, and the Discussion mentions CD19-CARs incorporating 4-1BB. Neither section establishes that all approved CAR T-cell products are second-generation or use one of those domains; this phase 1 trial is not a survey of approved products. No page numbers are available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Most clinical protocols and all commercially approved therapies have relied on viral vectors to deliver CAR transgenes into T cells.

    “Further, most clinical protocols, and all the commercially approved therapies, have relied on viral vectors to deliver CAR transgenes into T cells (9-14,24-26).”

    From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [14]

    The Methods > Procedures section (page not provided) says this clinical trial used a retroviral vector to manufacture CD19-CAR T cells. It does not establish that most clinical protocols or all commercially approved CAR T-cell therapies use viral vectors. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing.

    “First, most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing (9-18,21,22).”

    From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [14]

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Authors
Lee, D. W., Kochenderfer, J. N., Stetler-Stevenson, M., Cui, Y. K., Delbrook, C., Feldman, S. A., Fry, T. J., Orentas, R., Sabatino, M., Shah, N. N., Steinberg, S. M., Stroncek, D., Tschernia, N., Yuan, C., Zhang, H., Zhang, L., Rosenberg, S. A., Wayne, A. S., & Mackall, C. L.
Affiliations
  • National Institutes of Health (US)
  • National Cancer Institute (US)
  • University of Nevada, Reno (US)
  • University of Southern California (US)
Corresponding author
Mackall, Crystal L
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2015-02
Volume
385
Issue
9967
Pages
517-528
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(14)61403-3
PMC
PMC7065359
OpenAlex
W2129702476
Cited by
2,898
References
37
Citations by year
2026: 86 · 2025: 154 · 2024: 175 · 2023: 217 · 2022: 275 · 2021: 311 · 2020: 350 · 2019: 317 · 2018: 315 · 2017: 314 · 2016: 232 · 2015: 134 · 2014: 8 · 2013: 1 · 2012: 2
FWCI
103.68
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • St. Baldrick's Foundation
  • Entertainment Industry Foundation
  • National Institutes of Health
  • National Cancer Institute (Z01BC011072, Z01BC010566, Z01BC011024)
  • National Institute of Allergy and Infectious Diseases
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
CD19 chimeric antigen receptor, CAR T-cell therapy, acute lymphoblastic leukemia, non-Hodgkin lymphoma, relapsed or refractory B-cell malignancies, maximum tolerated dose, cytokine release syndrome, neurotoxicity, non-relapse mortality, fludarabine and cyclophosphamide conditioning
MeSH terms
Adolescent, Adult, Child, Child, Preschool, Chimera, Feasibility Studies, Female, Humans, Infant, Lymphoma, Non-Hodgkin, Male, Receptors, Antigen, T-Cell, T-Lymphocytes, Cohort Studies, Treatment Outcome, Antigens, CD19, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Young Adult, Cell- and Tissue-Based Therapy

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