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 van Mil; Monique C Minnema; Zsolt Sebestyén; Victor Peperzak

doi:10.1038/s41467-025-59818-8

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 van Mil, Monique C MinnemaZsolt Sebestyén, Victor Peperzak^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	4638
Number of pages	12
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-59818-8
Publication status	Published - 19 May 2025

Keywords

Animals
Apoptosis/immunology
B-Cell Maturation Antigen/immunology
Cell Line, Tumor
Female
Granzymes/genetics
Humans
Immunotherapy, Adoptive/methods
Mice
Mice, Inbred NOD
Multiple Myeloma/therapy
Myeloid Cell Leukemia Sequence 1 Protein/metabolism
Proto-Oncogene Proteins c-bcl-2/metabolism
Receptors, Chimeric Antigen/immunology
T-Lymphocytes/immunology
Xenograft Model Antitumor Assays

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Kimman, T., Cuenca, M., Tieland, R. G., Rockx-Brouwer, D., Janssen, J., Motais, B., Slomp, A., Pleijte, C., Heijhuurs, S., Meringa, A. D., Boschloo, W., Bosma, D. M., Kroos, S., Lo Presti, V., Sluijter, J. P. G., Nierkens, S., Bovenschen, N., Kuball, J., van Mil, A., ... Peperzak, V. (2025). Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation. Nature Communications, 16(1), Article 4638. https://doi.org/10.1038/s41467-025-59818-8

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title = "Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation",

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.",

keywords = "Animals, Apoptosis/immunology, B-Cell Maturation Antigen/immunology, Cell Line, Tumor, Female, Granzymes/genetics, Humans, Immunotherapy, Adoptive/methods, Mice, Mice, Inbred NOD, Multiple Myeloma/therapy, Myeloid Cell Leukemia Sequence 1 Protein/metabolism, Proto-Oncogene Proteins c-bcl-2/metabolism, Receptors, Chimeric Antigen/immunology, T-Lymphocytes/immunology, Xenograft Model Antitumor Assays",

author = "Thomas Kimman and Marta Cuenca and Tieland, {Ralph G} and Dedeke Rockx-Brouwer and Jasmijn Janssen and Benjamin Motais and Anne Slomp and Corine Pleijte and Sabine Heijhuurs and Meringa, {Angelo D} and Wendy Boschloo and Bosma, {Douwe Mt} and Sanne Kroos and {Lo Presti}, Vania and Sluijter, {Joost P G} and Stefan Nierkens and Niels Bovenschen and J{\"u}rgen Kuball and {van Mil}, Alain and Minnema, {Monique C} and Zsolt Sebesty{\'e}n and Victor Peperzak",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = may,

day = "19",

doi = "10.1038/s41467-025-59818-8",

language = "English",

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Kimman, T, Cuenca, M, Tieland, RG, Rockx-Brouwer, D, Janssen, J, Motais, B, Slomp, A, Pleijte, C, Heijhuurs, S, Meringa, AD, Boschloo, W, Bosma, DM, Kroos, S, Lo Presti, V, Sluijter, JPG , Nierkens, S , Bovenschen, N , Kuball, J , van Mil, A , Minnema, MC , Sebestyén, Z & Peperzak, V 2025, 'Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation', Nature Communications, vol. 16, no. 1, 4638. https://doi.org/10.1038/s41467-025-59818-8

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T1 - Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation

AU - Kimman, Thomas

AU - Cuenca, Marta

AU - Tieland, Ralph G

AU - Rockx-Brouwer, Dedeke

AU - Janssen, Jasmijn

AU - Motais, Benjamin

AU - Slomp, Anne

AU - Pleijte, Corine

AU - Heijhuurs, Sabine

AU - Meringa, Angelo D

AU - Boschloo, Wendy

AU - Bosma, Douwe Mt

AU - Kroos, Sanne

AU - Lo Presti, Vania

AU - Sluijter, Joost P G

AU - Nierkens, Stefan

AU - Bovenschen, Niels

AU - Kuball, Jürgen

AU - van Mil, Alain

AU - Minnema, Monique C

AU - Sebestyén, Zsolt

AU - Peperzak, Victor

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/5/19

Y1 - 2025/5/19

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis/immunology

KW - B-Cell Maturation Antigen/immunology

KW - Cell Line, Tumor

KW - Female

KW - Granzymes/genetics

KW - Humans

KW - Immunotherapy, Adoptive/methods

KW - Mice

KW - Mice, Inbred NOD

KW - Multiple Myeloma/therapy

KW - Myeloid Cell Leukemia Sequence 1 Protein/metabolism

KW - Proto-Oncogene Proteins c-bcl-2/metabolism

KW - Receptors, Chimeric Antigen/immunology

KW - T-Lymphocytes/immunology

KW - Xenograft Model Antitumor Assays

U2 - 10.1038/s41467-025-59818-8

DO - 10.1038/s41467-025-59818-8

M3 - Article

C2 - 40389394

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4638

ER -

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

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Keywords

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