Engineering BCMA CAR T cells for myeloma-targeted cargo delivery

Kimman, T.; Cuenca, M.; Slomp, A.; Tieland, R. G.; Rockx-Brouwer, D.; Heijhuurs, S.; Meringa, A. D.; Boschloo, W.; Bosma, D. M.; Kroos, S.; lo Presti, V.; Nierkens, S.; Bovenschen, N.; Kuball, J.; Minnema, M. C.; Sebestyen, Z.; Peperzak, V.

doi:10.1101/2024.02.14.580301

bioRxiv · 10.1101/2024.02.14.580301

Engineering BCMA CAR T cells for myeloma-targeted cargo delivery

Kimman, T.·Cuenca, M.·Slomp, A.·Tieland, R. G.·Rockx-Brouwer, D.·Heijhuurs, S.·Meringa, A. D.·Boschloo, W.·Bosma, D. M.·Kroos, S.·lo Presti, V.·Nierkens, S.·Bovenschen, N.·Kuball, J.·Minnema, M. C.·Sebestyen, Z.·Peperzak, V.

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Abstract

Clinical responses with chimeric antigen receptor (CAR) T cells are encouraging, however, primary resistance and relapse after therapy prevent durable remission in a large fraction of cancer patients. One of the underlying causes comprises apoptosis resistance mechanisms in cancer cells that limit killing by CAR T cells. Therefore, we developed a technology that boosts tumor cell apoptosis induced by CAR T cells. We reveal that B cell maturation antigen (BCMA) CAR T cells equipped with a granzyme B-NOXA fusion construct improves killing of multiple myeloma (MM) cells, both in vitro and in a xenograft mouse model, by localizing NOXA to cytotoxic granules that are released into cancer cells upon contact. Since MM cells critically depend on MCL-1 expression, inhibition by its natural ligand NOXA effectively induces apoptosis. Overall, this strategy allows specific delivery of cargo into cancer cells and improves killing efficacy of CAR T cells in a tailor-made manner.

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Kimman, T., Cuenca, M., Slomp, A., Tieland, R. G., Rockx-Brouwer, D., Heijhuurs, S., Meringa, A. D., Boschloo, W., Bosma, D. M., Kroos, S., lo Presti, V., Nierkens, S., Bovenschen, N., Kuball, J., Minnema, M. C., Sebestyen, Z., Peperzak, V.. 2024-02-17. Engineering BCMA CAR T cells for myeloma-targeted cargo delivery. https://doi.org/10.1101/2024.02.14.580301

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