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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

Author

Listed:
  • Raymond Hall Yip Louie

    (UNSW Sydney
    UNSW Sydney
    UNSW Sydney)

  • Curtis Cai

    (UNSW Sydney
    UNSW Sydney)

  • Jerome Samir

    (UNSW Sydney
    UNSW Sydney)

  • Mandeep Singh

    (Garvan Institute for Medical Research)

  • Ira W. Deveson

    (Garvan Institute for Medical Research)

  • James M. Ferguson

    (Garvan Institute for Medical Research)

  • Timothy G. Amos

    (Garvan Institute for Medical Research)

  • Helen Marie McGuire

    (The University of Sydney
    The University of Sydney
    Faculty of Medicine and Health, The University of Sydney)

  • Kavitha Gowrishankar

    (Westmead Hospital
    Westmead Institute for Medical Research)

  • Thiruni Adikari

    (UNSW Sydney
    UNSW Sydney)

  • Robert Balderas

    (Becton Dickinson)

  • Martina Bonomi

    (UNSW Sydney
    University of Bologna)

  • Marco Ruella

    (University of Pennsylvania)

  • David Bishop

    (Westmead Hospital
    Westmead Institute for Medical Research
    The University of Sydney)

  • David Gottlieb

    (Westmead Hospital
    Westmead Institute for Medical Research
    The University of Sydney)

  • Emily Blyth

    (Westmead Hospital
    Westmead Institute for Medical Research
    The University of Sydney)

  • Kenneth Micklethwaite

    (Westmead Hospital
    Westmead Institute for Medical Research
    The University of Sydney
    NSW Health Pathology Blood Transplant and Cell Therapies Laboratory – ICPMR Westmead)

  • Fabio Luciani

    (UNSW Sydney
    UNSW Sydney
    Garvan Institute for Medical Research)

Abstract

Chimeric antigen receptor (CAR) T cell therapy is effective in treating B cell malignancies, but factors influencing the persistence of functional CAR+ T cells, such as product composition, patients’ lymphodepletion, and immune reconstitution, are not well understood. To shed light on this issue, here we conduct a single-cell multi-omics analysis of transcriptional, clonal, and phenotypic profiles from pre- to 1-month post-infusion of CAR+ and CAR− T cells from patients from a CARTELL study (ACTRN12617001579381) who received a donor-derived 4-1BB CAR product targeting CD19. Following infusion, CAR+ T cells and CAR− T cells shows similar differentiation profiles with clonally expanded populations across heterogeneous phenotypes, demonstrating clonal lineages and phenotypic plasticity. We validate these findings in 31 patients with large B cell lymphoma treated with CD19 CAR T therapy. For these patients, we identify using longitudinal mass-cytometry data an association between NK-like subsets and clinical outcomes at 6 months with both CAR+ and CAR− T cells. These results suggest that non-CAR-derived signals can provide information about patients’ immune recovery and be used as correlate of clinically relevant parameters.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43656-7
    DOI: 10.1038/s41467-023-43656-7
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    References listed on IDEAS

    as
    1. Curtis Cai & Jerome Samir & Mehdi R. Pirozyan & Thiruni N. Adikari & Money Gupta & Preston Leung & Brendan Hughes & Willem Byl & Simone Rizzetto & Auda Elthala & Elizabeth Keoshkerian & Jean-Louis Pal, 2022. "Identification of human progenitors of exhausted CD8+ T cells associated with elevated IFN-γ response in early phase of viral infection," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Rachel C. Lynn & Evan W. Weber & Elena Sotillo & David Gennert & Peng Xu & Zinaida Good & Hima Anbunathan & John Lattin & Robert Jones & Victor Tieu & Surya Nagaraja & Jeffrey Granja & Charles F. A. B, 2019. "c-Jun overexpression in CAR T cells induces exhaustion resistance," Nature, Nature, vol. 576(7786), pages 293-300, December.
    3. 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. "Author Correction: Decade-long leukaemia remissions with persistence of CD4+ CAR T cells," Nature, Nature, vol. 612(7941), pages 22-22, December.
    4. Jordan W. Squair & Matthieu Gautier & Claudia Kathe & Mark A. Anderson & Nicholas D. James & Thomas H. Hutson & Rémi Hudelle & Taha Qaiser & Kaya J. E. Matson & Quentin Barraud & Ariel J. Levine & Gio, 2021. "Confronting false discoveries in single-cell differential expression," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. 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.
    6. Mandeep Singh & Ghamdan Al-Eryani & Shaun Carswell & James M. Ferguson & James Blackburn & Kirston Barton & Daniel Roden & Fabio Luciani & Tri Giang Phan & Simon Junankar & Katherine Jackson & Christo, 2019. "High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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