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Decade-long leukaemia remissions with persistence of CD4+ CAR T cells

Author

Listed:
  • J. Joseph Melenhorst

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

  • Gregory M. Chen

    (University of Pennsylvania)

  • Meng Wang

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • David L. Porter

    (University of Pennsylvania
    Department of Medicine, University of Pennsylvania)

  • Changya Chen

    (Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • McKensie A. Collins

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

  • Peng Gao

    (Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Shovik Bandyopadhyay

    (University of Pennsylvania)

  • Hongxing Sun

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Ziran Zhao

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Stefan Lundh

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Iulian Pruteanu-Malinici

    (Novartis Institute for Biomedical Research)

  • Christopher L. Nobles

    (University of Pennsylvania)

  • Sayantan Maji

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Noelle V. Frey

    (University of Pennsylvania)

  • Saar I. Gill

    (University of Pennsylvania)

  • Alison W. Loren

    (University of Pennsylvania)

  • Lifeng Tian

    (University of Pennsylvania
    University of Pennsylvania)

  • Irina Kulikovskaya

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Minnal Gupta

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • David E. Ambrose

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Megan M. Davis

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Joseph A. Fraietta

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

  • Jennifer L. Brogdon

    (Novartis Institute for Biomedical Research)

  • Regina M. Young

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Anne Chew

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Bruce L. Levine

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Donald L. Siegel

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Cécile Alanio

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • E. John Wherry

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Frederic D. Bushman

    (University of Pennsylvania)

  • Simon F. Lacey

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Kai Tan

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

  • Carl H. June

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

Abstract

The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1–7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1–4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.

Suggested Citation

  • J. Joseph Melenhorst & Gregory M. Chen & Meng Wang & David L. Porter & Changya Chen & McKensie A. Collins & Peng Gao & Shovik Bandyopadhyay & Hongxing Sun & Ziran Zhao & Stefan Lundh & Iulian Pruteanu, 2022. "Decade-long leukaemia remissions with persistence of CD4+ CAR T cells," Nature, Nature, vol. 602(7897), pages 503-509, February.
  • Handle: RePEc:nat:nature:v:602:y:2022:i:7897:d:10.1038_s41586-021-04390-6
    DOI: 10.1038/s41586-021-04390-6
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    Citations

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    Cited by:

    1. Ugur Uslu & Lijun Sun & Sofia Castelli & Amanda V. Finck & Charles-Antoine Assenmacher & Regina M. Young & Zhijian J. Chen & Carl H. June, 2024. "The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Elisa Landoni & Mark G. Woodcock & Gabriel Barragan & Gabriele Casirati & Vincenzo Cinella & Simone Stucchi & Leah M. Flick & Tracy A. Withers & Hanna Hudson & Giulia Casorati & Paolo Dellabona & Piet, 2024. "IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Ariel Isser & Aliyah B. Silver & Hawley C. Pruitt & Michal Mass & Emma H. Elias & Gohta Aihara & Si-Sim Kang & Niklas Bachmann & Ying-Yu Chen & Elissa K. Leonard & Joan G. Bieler & Worarat Chaisawangw, 2022. "Nanoparticle-based modulation of CD4+ T cell effector and helper functions enhances adoptive immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Jianting Long & Xihe Chen & Mian He & Shudan Ou & Yunhe Zhao & Qingjia Yan & Minjun Ma & Jingyu Chen & Xuping Qin & Xiangjun Zhou & Junjun Chu & Yanyan Han, 2024. "HLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Tomás A. Martins & Deniz Kaymak & Nazanin Tatari & Fiona Gerster & Sabrina Hogan & Marie-Françoise Ritz & Valerio Sabatino & Ronja Wieboldt & Ewelina M. Bartoszek & Marta McDaid & Alexandra Gerber & A, 2024. "Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    6. Rocío Castellanos-Rueda & Raphaël B. Roberto & Florian Bieberich & Fabrice S. Schlatter & Darya Palianina & Oanh T. P. Nguyen & Edo Kapetanovic & Heinz Läubli & Andreas Hierlemann & Nina Khanna & Sai , 2022. "speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Ulrich Blache & Georg Popp & Anna Dünkel & Ulrike Koehl & Stephan Fricke, 2022. "Potential solutions for manufacture of CAR T cells in cancer immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-5, December.
    8. Raymond Hall Yip Louie & Curtis Cai & Jerome Samir & Mandeep Singh & Ira W. Deveson & James M. Ferguson & Timothy G. Amos & Helen Marie McGuire & Kavitha Gowrishankar & Thiruni Adikari & Robert Balder, 2023. "CAR+ and CAR− T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Dhivya Sridaran & Surbhi Chouhan & Kiran Mahajan & Arun Renganathan & Cody Weimholt & Shambhavi Bhagwat & Melissa Reimers & Eric H. Kim & Manish K. Thakur & Muhammad A. Saeed & Russell K. Pachynski & , 2022. "Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    10. Dan Li & Ruixue Wang & Tianyuzhou Liang & Hua Ren & Chaelee Park & Chin-Hsien Tai & Weiming Ni & Jing Zhou & Sean Mackay & Elijah Edmondson & Javed Khan & Brad St Croix & Mitchell Ho, 2023. "Camel nanobody-based B7-H3 CAR-T cells show high efficacy against large solid tumours," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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