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Notably, allogeneic stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have contributed to enhanced quality of life. Recently, a promising avenue has emerged with chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA), expressed widely on MM cells. To mitigate risks associated with allogenic T cells, we investigated the potential of BCMA CAR expression in natural killer cells (NKs), known for potent cytotoxicity and minimal side effects. Using the NK-92 cell line, we co-expressed BCMA CAR and soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) employing the piggyBac transposon system. Engineered NK cells (CAR-NK-92-TRAIL) demonstrated robust cytotoxicity against a panel of MM cell lines and primary patient samples, outperforming unmodified NK-92 cells with a mean difference in viability of 45.1% (\u00b126.1%, depending on the target cell line). Combination therapy was explored with the proteasome inhibitor bortezomib (BZ) and \u03b3-secretase inhibitors (GSIs), leading to a significant synergistic effect in combination with CAR-NK-92-TRAIL cells. This synergy was evident in cytotoxicity assays where a notable decrease in MM cell viability was observed in combinatorial therapy compared to single treatment. In summary, our study demonstrates the therapeutic potential of the CAR-NK-92-TRAIL cells for the treatment of MM. The synergistic impact of combining these engineered NK cells with BZ and GSI supports further development of allogeneic CAR-based products for effective MM therapy.<\/jats:p>","DOI":"10.3390\/cells12232748","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T09:39:12Z","timestamp":1701337152000},"page":"2748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["NK92 Expressing Anti-BCMA CAR and Secreted TRAIL for the Treatment of Multiple Myeloma: Preliminary In Vitro Assessment"],"prefix":"10.3390","volume":"12","author":[{"given":"Benjamin","family":"Motais","sequence":"first","affiliation":[{"name":"Department of Haematooncology, Faculty of Medicine, University of Ostrava, 703 00 Ostrava, Czech Republic"},{"name":"Faculty of Science, University of Ostrava, 701 00 Ostrava, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6378-4696","authenticated-orcid":false,"given":"Sandra","family":"Charv\u00e1tov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Haematooncology, Faculty of Medicine, University of Ostrava, 703 00 Ostrava, Czech Republic"},{"name":"Faculty of Science, University of Ostrava, 701 00 Ostrava, Czech Republic"},{"name":"Department of Haematooncology, University Hospital Ostrava, 708 00 Ostrava, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Walek","sequence":"additional","affiliation":[{"name":"Department of Haematooncology, Faculty of Medicine, University of Ostrava, 703 00 Ostrava, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"H\u00e1jek","sequence":"additional","affiliation":[{"name":"Department of Haematooncology, Faculty of Medicine, University of Ostrava, 703 00 Ostrava, Czech Republic"},{"name":"Department of Haematooncology, University Hospital Ostrava, 708 00 Ostrava, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-4048","authenticated-orcid":false,"given":"Juli R.","family":"Bag\u00f3","sequence":"additional","affiliation":[{"name":"Department of Haematooncology, Faculty of Medicine, University of Ostrava, 703 00 Ostrava, Czech Republic"},{"name":"Department of Haematooncology, University Hospital Ostrava, 708 00 Ostrava, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6887","DOI":"10.4081\/hr.2017.6887","article-title":"Impact of CRAB Symptoms in Survival of Patients with Symptomatic Myeloma in Novel Agent Era","volume":"9","author":"Nakaya","year":"2017","journal-title":"Hematol. 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