IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v558y2018i7709d10.1038_s41586-018-0178-z.html
   My bibliography  Save this article

Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells

Author

Listed:
  • Joseph A. Fraietta

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Christopher L. Nobles

    (University of Pennsylvania)

  • Morgan A. Sammons

    (University of Pennsylvania
    University at Albany, State University of New York)

  • Stefan Lundh

    (University of Pennsylvania
    University of Pennsylvania)

  • Shannon A. Carty

    (University of Pennsylvania
    University of Michigan)

  • Tyler J. Reich

    (University of Pennsylvania
    University of Pennsylvania)

  • Alexandria P. Cogdill

    (University of Pennsylvania
    University of Pennsylvania)

  • Jennifer J. D. Morrissette

    (University of Pennsylvania)

  • Jamie E. DeNizio

    (University of Pennsylvania
    University of Pennsylvania)

  • Shantan Reddy

    (University of Pennsylvania)

  • Young Hwang

    (University of Pennsylvania)

  • Mercy Gohil

    (University of Pennsylvania
    University of Pennsylvania)

  • Irina Kulikovskaya

    (University of Pennsylvania
    University of Pennsylvania)

  • Farzana Nazimuddin

    (University of Pennsylvania
    University of Pennsylvania)

  • Minnal Gupta

    (University of Pennsylvania
    University of Pennsylvania)

  • Fang Chen

    (University of Pennsylvania
    University of Pennsylvania)

  • John K. Everett

    (University of Pennsylvania)

  • Katherine A. Alexander

    (University of Pennsylvania)

  • Enrique Lin-Shiao

    (University of Pennsylvania)

  • Marvin H. Gee

    (Stanford University School of Medicine)

  • Xiaojun Liu

    (University of Pennsylvania
    University of Pennsylvania)

  • Regina M. Young

    (University of Pennsylvania
    University of Pennsylvania)

  • David Ambrose

    (University of Pennsylvania
    University of Pennsylvania)

  • Yan Wang

    (University of Pennsylvania
    University of Pennsylvania)

  • Jun Xu

    (University of Pennsylvania
    University of Pennsylvania)

  • Martha S. Jordan

    (University of Pennsylvania
    University of Pennsylvania)

  • Katherine T. Marcucci

    (University of Pennsylvania
    University of Pennsylvania)

  • Bruce L. Levine

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • K. Christopher Garcia

    (Stanford University School of Medicine)

  • Yangbing Zhao

    (University of Pennsylvania
    University of Pennsylvania)

  • Michael Kalos

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • David L. Porter

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Rahul M. Kohli

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Simon F. Lacey

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Shelley L. Berger

    (University of Pennsylvania)

  • Frederic D. Bushman

    (University of Pennsylvania)

  • Carl H. June

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • J. Joseph Melenhorst

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies1–3. In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells4,5. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient’s second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient’s CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.

Suggested Citation

  • Joseph A. Fraietta & Christopher L. Nobles & Morgan A. Sammons & Stefan Lundh & Shannon A. Carty & Tyler J. Reich & Alexandria P. Cogdill & Jennifer J. D. Morrissette & Jamie E. DeNizio & Shantan Redd, 2018. "Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells," Nature, Nature, vol. 558(7709), pages 307-312, June.
  • Handle: RePEc:nat:nature:v:558:y:2018:i:7709:d:10.1038_s41586-018-0178-z
    DOI: 10.1038/s41586-018-0178-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-018-0178-z
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-018-0178-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Jingjing Ren & Xiaofeng Liao & Julia M. Lewis & Jungsoo Chang & Rihao Qu & Kacie R. Carlson & Francine Foss & Michael Girardi, 2024. "Generation and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Nan Li & Alex Quan & Dan Li & Jiajia Pan & Hua Ren & Gerard Hoeltzel & Natalia Val & Dana Ashworth & Weiming Ni & Jing Zhou & Sean Mackay & Stephen M. Hewitt & Raul Cachau & Mitchell Ho, 2023. "The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Meagan R. Rollins & Jackson F. Raynor & Ebony A. Miller & Jonah Z. Butler & Ellen J. Spartz & Walker S. Lahr & Yun You & Adam L. Burrack & Branden S. Moriarity & Beau R. Webber & Ingunn M. Stromnes, 2023. "Germline T cell receptor exchange results in physiological T cell development and function," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:558:y:2018:i:7709:d:10.1038_s41586-018-0178-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.