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Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"the Paula and Rodger Riney Foundation"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"the Adelson Medical Research Foundation and the Paula and Rodger Riney Foundation"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer 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GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4\u2009h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.e., 2\u2009nM LY-411575 or 1\u2009\u03bcM DAPT, robustly increased mBCMA densities on CD138<jats:sup>+<\/jats:sup> but not CD3<jats:sup>+<\/jats:sup> patient cells, concomitantly with minimum soluble\/shed BCMA (sBCMA) in 1 day-culture supernatants. In ex vivo MM-T-cell co-cultures, GSIs overcame sBCMA-inhibited MM cell lysis and further enhanced autologous patient MM cell lysis induced by BCMAxCD3 BisAbs, accompanied by significantly enhanced cytolytic markers (CD107a, IFN\u03b3, IL2, and TNF\u03b1) in patient T cells. In longer 7 day-co-cultures, LY-411575 minimally affected BCMAxCD3 BisAb (PL33)-induced transient expression of checkpoint (PD1, TIGIT, TIM3, LAG3) and co-stimulatory (41BB, CD28) proteins, as well as time-dependent increases in % effector memory\/central memory subsets and CD8\/CD4 ratios in patient T cells. Importantly, LY41157 rapidly cleared sBCMA from circulation of MM-bearing NSG mice reconstituted with human T cells and significantly enhanced anti-MM efficacy of PL33 with prolonged host survival. Taken together, these results further support ongoing combination BCMA-targeting immunotherapies with GSI clinical studies to improve patient outcome.<\/jats:p>","DOI":"10.1038\/s41408-022-00716-3","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T07:03:16Z","timestamp":1660633396000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["\u03b3-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1648-0427","authenticated-orcid":false,"given":"Hailin","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengteng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijie","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Feng","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Aardalen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adwait","family":"Oka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joni","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4673-8214","authenticated-orcid":false,"given":"Mike","family":"Daley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haihui","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7344-9795","authenticated-orcid":false,"given":"Nikhil","family":"Munshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth C.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6199-3569","authenticated-orcid":false,"given":"Yu-Tzu","family":"Tai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"key":"716_CR1","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.2217\/imt.15.77","volume":"7","author":"YT Tai","year":"2015","unstructured":"Tai YT, Anderson KC. 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NCM serves on advisory boards to Millennium-Takeda, Celgene, and Novartis and is a Scientific Founder of Oncopep. NCM serves on advisory boards\/consultant to Takeda, BMS, Celgene, Janssen, Amgen, AbbVie, Oncopep, Karyopharm, Adaptive Biotechnology, and Novartis and holds equity ownership in Oncopep. KCA serves on advisory boards to Pfizer, Amgen, AstraZeneca, Janssen, Precision Biosciences, Window, and Starton, and is a scientific founder of OncoPep, C4 Therapeutics, Raqia, and NextRNA. All other authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"118"}}