Hailin, Chen, Tengteng, Yu, Liang, Lin, Lijie, Xing, Shih-Feng, Cho, Kenneth, Wen, Aardalen, Kimberly, Ok, Adwait, Lam, Joni, Daley, Michael, Lu, Haihui, Nikhil, Munshi, Kenneth, Anderson and Yu-Tzu, Tai (2022) γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation. Blood cancer journal, 12 (8). p. 118. ISSN 2044-5385

Abstract

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.

Item Type:	Article
Keywords:	Amyloid Precursor Protein Secretases Animals Antibodies, Bispecific B-Cell Maturation Antigen Humans Mice Multiple Myeloma T-Lymphocytes
Date Deposited:	28 Dec 2022 00:45
Last Modified:	28 Dec 2022 00:45
URI:	https://oak.novartis.com/id/eprint/47335