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Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation

Author

Listed:
  • Thomas Kimman

    (University Medical Center Utrecht)

  • Marta Cuenca

    (University Medical Center Utrecht)

  • Ralph G. Tieland

    (University Medical Center Utrecht)

  • Dedeke Rockx-Brouwer

    (University Medical Center Utrecht)

  • Jasmijn Janssen

    (University Medical Center Utrecht)

  • Benjamin Motais

    (University Medical Center Utrecht
    University Medical Centre Utrecht)

  • Anne Slomp

    (University Medical Center Utrecht)

  • Corine Pleijte

    (University Medical Center Utrecht)

  • Sabine Heijhuurs

    (University Medical Center Utrecht)

  • Angelo D. Meringa

    (University Medical Center Utrecht)

  • Wendy Boschloo

    (University Medical Center Utrecht)

  • Douwe MT Bosma

    (University Medical Center Utrecht)

  • Sanne Kroos

    (University Medical Center Utrecht)

  • Vania lo Presti

    (University Medical Center Utrecht
    Princess Máxima Center for Pediatric Oncology)

  • Joost P. G. Sluijter

    (University Medical Center Utrecht
    Utrecht University)

  • Stefan Nierkens

    (University Medical Center Utrecht
    Princess Máxima Center for Pediatric Oncology
    Princess Máxima Center for Pediatric Oncology)

  • Niels Bovenschen

    (University Medical Center Utrecht
    Utrecht University
    University Medical Centre Utrecht)

  • Jürgen Kuball

    (University Medical Center Utrecht
    University Medical Centre Utrecht
    Utrecht University)

  • Alain Mil

    (University Medical Center Utrecht
    Utrecht University)

  • Monique C. Minnema

    (University Medical Centre Utrecht
    Utrecht University)

  • Zsolt Sebestyén

    (University Medical Center Utrecht
    Utrecht University)

  • Victor Peperzak

    (University Medical Center Utrecht
    Utrecht University)

Abstract

Clinical responses with chimeric antigen receptor (CAR) T cells are encouraging, but primary resistance and relapse after therapy prevent durable remission in many patients with cancer, with apoptosis resistance in cancer cells that limits killing by CAR T cells being a potential cause. Here we aim to boost tumor cell apoptosis induced by CAR T cells and find that anti-B cell maturation antigen (BCMA) CAR T cells over-expressing a granzyme B-NOXA fusion protein show improved killing of multiple myeloma (MM) cells in vitro and in xenograft mouse models in vivo. Mechanistically, such an enhancement is mediated by localizing NOXA to cytotoxic granules that are released into cancer cells upon contact. In MM cells, inhibition of MCL-1, an anti-apoptotic factor, by its natural ligand NOXA effectively induces apoptosis. Our data thus show that endowing granzyme B-NOXA expression to CAR T cells improves their killing efficacy, thereby presenting a potential generalizable enhancement for CAR T-mediated anti-cancer immunity.

Suggested Citation

  • Thomas Kimman & Marta Cuenca & Ralph G. Tieland & Dedeke Rockx-Brouwer & Jasmijn Janssen & Benjamin Motais & Anne Slomp & Corine Pleijte & Sabine Heijhuurs & Angelo D. Meringa & Wendy Boschloo & Douwe, 2025. "Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59818-8
    DOI: 10.1038/s41467-025-59818-8
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    References listed on IDEAS

    as
    1. 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.
    2. Joseph T. Opferman & Anthony Letai & Caroline Beard & Mia D. Sorcinelli & Christy C. Ong & Stanley J. Korsmeyer, 2003. "Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1," Nature, Nature, vol. 426(6967), pages 671-676, 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. "Decade-long leukaemia remissions with persistence of CD4+ CAR T cells," Nature, Nature, vol. 602(7897), pages 503-509, February.
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