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

Summary

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. © 2025. The Author(s).

Authors 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
Journal Nature communications
Publication Date 2025 May 19;16(1):4638
PubMed 40389394
PubMed Central PMC12089368
DOI 10.1038/s41467-025-59818-8

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