γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation

• Published in: Blood cancer journal (New York) Vol. 12; no. 8; p. 118
• Main Authors: Chen, Hailin, Yu, Tengteng, Lin, Liang, Xing, Lijie, Cho, Shih-Feng, Wen, Kenneth, Aardalen, Kimberly, Oka, Adwait, Lam, Joni, Daley, Mike, Lu, Haihui, Munshi, Nikhil, Anderson, Kenneth C, Tai, Yu-Tzu
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 16.08.2022; Nature Publishing Group UK; Nature Publishing Group
• Subjects: Amyloid Precursor Protein Secretases; Animals; Antibodies; Antibodies, Bispecific - therapeutic use; Antigens; B-Cell Maturation Antigen; Biomedical research; Cancer therapies; Cloning; Cytotoxicity; Drug dosages; Hematology; Hospitals; Humans; Immunotherapy; Laboratory animals; Lymphocytes; Medicine; Mice; Multiple myeloma; Multiple Myeloma - drug therapy; Patients; T-Lymphocytes; Variance analysis
• ISSN: 2044-5385; 2044-5385
• DOI: 10.1038/s41408-022-00716-3

We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4 h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.e., 2 nM LY-411575 or 1 μM DAPT, robustly increased mBCMA densities on CD138 but not CD3 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, IFNγ, IL2, and TNFα) 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.