CoChat
Sign Up
Cited by 3,565CAR-T cell therapy researchChronic Lymphocytic Leukemia ResearchVirus-based gene therapy research

Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia

Open access
Porter, David L., Levine, Bruce L., Kalos, Michael, Bagg, Adam, June, Carl H.·2011·New England Journal of Medicine
DOI 10.1056/nejmoa1103849PMC PMC3387277
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1056/nejmoa1103849

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [11]

    The Discussion (page unavailable) identifies the authors’ CD137 (4-1BB) CAR as second-generation and mentions a separate CD28-linked CAR trial. The paper supports the role of costimulation in expansion and persistence, but it does not assess approved products or establish that all approved CAR T-cell products have either design. (LLM, conf=0.87)

    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 [11]

    The Methods (Study Procedures; page unavailable) describe this clinical trial's use of a lentiviral vector, and the Discussion says the authors used HIV-derived lentiviral vectors. The paper therefore supports an example of a clinical protocol using viral delivery, but it does not establish that most protocols or all commercially approved therapies did so. (LLM, conf=0.88)

    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 [11]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 25

  1. [1]Gross G Waks T Eshhar Z Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity Proc Natl Acad Sci U S A 1989 86 10024 8 2513569 PMC298636
  2. [2]Irving BA Weiss A The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways Cell 1991 64 891 901 1705867
  3. [3]Sadelain M Brentjens R Rivière I The promise and potential pitfalls of chimeric antigen receptors Curr Opin Immunol 2009 21 215 23 19327974 PMC5548385
  4. [4]Jena B Dotti G Cooper LJ Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor Blood 2010 116 1035 44 20439624 PMC2938125
  5. [5]Milone MC Fish JD Carpenito C Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo Mol Ther 2009 17 1453 64 19384291 PMC2805264
  6. [6]Carpenito C Milone MC Hassan R Control of large, established tumor xe-nografts with genetically retargeted human T cells containing CD28 and CD137 domains Proc Natl Acad Sci U S A 2009 106 3360 5 19211796 PMC2651342
  7. [7]Uckun FM Jaszcz W Ambrus JL Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins Blood 1988 71 13 29 3257143
  8. [8]Porter DL Levine BL Bunin N A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation Blood 2006 107 1325 31 16269610
  9. [9]Lamanna N Kalaycio M Maslak P Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia J Clin Oncol 2006 24 1575 81 16520464
  10. [10]Baeksgaard L Sørensen J Acute tumor lysis syndrome in solid tumors — a case report and review of the literature Cancer Chemother Pharmacol 2003 51 187 92 12655435
  11. [11]Kohn DB Dotti G Brentjens R CARS on track in the clinic Mol Ther 2011 19 432 8 21358705 PMC3048197
  12. [12]June CH Blazar BR Riley JL Engineering lymphocyte subsets: tools, trials and tribulations Nat Rev Immunol 2009 9 704 16 19859065 PMC3412112
  13. [13]Kershaw MH Westwood JA Parker LL A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer Clin Cancer Res 2006 12 6106 15 17062687 PMC2154351
  14. [14]Till BG Jensen MC Wang J Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells Blood 2008 112 2261 71 18509084 PMC2532803
  15. [15]Pule MA Savoldo B Myers GD Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma Nat Med 2008 14 1264 70 18978797 PMC2749734
  16. [16]Brentjens R Yeh R Bernal Y Riviere I Sadelain M Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial Mol Ther 2010 18 666 8 20357779 PMC2862525
  17. [17]Morgan RA Yang JC Kitano M Dudley ME Laurencot C Rosenberg SA Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2 Mol Ther 2010 18 843 51 20179677 PMC2862534
  18. [18]Johnson LA Morgan RA Dudley ME Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen Blood 2009 114 535 46 19451549 PMC2929689
  19. [19]Klebanoff CA Khong HT Antony PA Palmer DC Restifo NP Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy Trends Immunol 2005 26 111 7 15668127 PMC1388277 Trends Immunol 2005 26 298 Erratum
  20. [21]Ramakrishnan R Assudani D Nagaraj S Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice J Clin Invest 2010 120 1111 24 20234093 PMC2846048
  21. [22]Molina A A decade of rituximab: improving survival outcomes in non-Hodgkin’s lymphoma Annu Rev Med 2008 59 237 50 18186705
  22. [23]Döhner H Fischer K Bentz M p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias Blood 1995 85 1580 9 7888675
  23. [24]Gribben JG Hosing C Maloney DG Stem cell transplantation for indolent lymphoma and chronic lymphocytic leukemia Biol Blood Marrow Transplant 2011 17 Suppl S63 S70 21195313 PMC3392079
  24. [25]Sorror ML Storer BE Maloney DG Sandmaier BM Martin PJ Storb R Out-comes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia Blood 2008 111 446 52 17916744 PMC2200822
  25. [26]Kalos M Levine BL Porter DL T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia Sci Transl Med 2011 3 95ra73 PMC3393096 21832238

Cited by

Sorted by citations

Authors
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A., & June, C. H.
Affiliations
Abramson Cancer Center (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2011-08-25
Volume
365
Issue
8
Pages
725-733
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1103849
PMC
PMC3387277
OpenAlex
W2130011407
Cited by
3,565
References
1
Citations by year
2026: 105 · 2025: 182 · 2024: 179 · 2023: 188 · 2022: 213 · 2021: 242 · 2020: 261 · 2019: 267 · 2018: 268 · 2017: 276 · 2016: 282 · 2015: 289 · 2014: 257 · 2013: 303 · 2012: 195
FWCI
127.08
Type
journal article
Language
en
Update notices
correction (2016-03-10)
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5k24ca117879-05)
  • National Eye Institute (PN2EY016586, 1PN2-EY016586, PN1EY016586)
  • National Cancer Institute (R01CA120409, K24 CA117879-01, K24-CA117879)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
chimeric antigen receptor T cells, chronic lymphocytic leukemia, CD19, lentiviral vectors, 4-1BB costimulation, refractory leukemia, tumor lysis syndrome, lymphopenia, hypogammaglobulinemia, complete remission, B-cell depletion, CAR T cell persistence
MeSH terms
Agammaglobulinemia, B-Lymphocytes, Bone Marrow, Chimera, Humans, Immunotherapy, Leukemia, Lymphoid, Male, Receptors, Antigen, T-Cell, Remission Induction, T-Lymphocytes, Tumor Lysis Syndrome, Lentivirus, Cytokines, Antigens, CD19

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review