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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月19日

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  • 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 M. T. Bosma,
  • Sanne Kroos,
  • Vania lo Presti,
  • Joost P. G. Sluijter,
  • Stefan Nierkens,
  • Niels Bovenschen,
  • Jürgen Kuball,
  • Alain van Mil,
  • Monique C. Minnema,
  • Zsolt Sebestyén,
  • Victor Peperzak

摘要

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.