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

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 MT Bosma, Sanne Kroos, Vania lo Presti, Joost P. G. Sluijter, Stefan Nierkens, Niels Bovenschen, Jürgen Kuball, Alain Mil, Monique C. Minnema, Zsolt Sebestyén and Victor Peperzak ()
Additional contact information
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
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
Joost P. G. Sluijter: University Medical Center Utrecht
Stefan Nierkens: University Medical Center Utrecht
Niels Bovenschen: University Medical Center Utrecht
Jürgen Kuball: University Medical Center Utrecht
Alain Mil: University Medical Center Utrecht
Monique C. Minnema: University Medical Centre Utrecht
Zsolt Sebestyén: University Medical Center Utrecht
Victor Peperzak: University Medical Center Utrecht

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59818-8

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