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.

我们在这里定义了 γ 分泌酶抑制剂 (GSI) 对 T 细胞依赖性 BCMA 特异性多发性骨髓瘤 (MM) 细胞裂解和双特异性抗体 (BisAb) 诱导的免疫调节作用的影响。GSIs 诱导的膜 BCMA (mBCMA) 积累在 4 小时内达到接近最大值，并在 MM 细胞系和患者 MM 细胞的研究期间持续超过 42 小时。GSI，即 2 nM LY-411575 或 1 μM DAPT，可显着增加 CD138 ⁺而非 CD3 ^{+上的 mBCMA 密度}患者细胞，伴随着 1 天培养上清液中的最低可溶性/脱落 BCMA (sBCMA)。在离体 MM-T 细胞共培养中，GSI 克服了 sBCMA 抑制的 MM 细胞裂解，并进一步增强了 BCMAxCD3 BisAb 诱导的自体患者 MM 细胞裂解，同时显着增强了细胞溶解标记物（CD107a、IFNγ、IL2 和 TNFα）患者 T 细胞。在更长的 7 天共培养中，LY-411575 对 BCMAxCD3 BisAb (PL33) 诱导的检查点（PD1、TIGIT、TIM3、LAG3）和共刺激（41BB、CD28）蛋白以及时间-患者 T 细胞中效应记忆/中央记忆亚群百分比和 CD8/CD4 比率的依赖性增加。重要的，LY41157 迅速清除了用人 T 细胞重组的携带 MM 的 NSG 小鼠循环中的 sBCMA，并显着增强了 PL33 的抗 MM 功效并延长了宿主存活期。总而言之，这些结果进一步支持正在进行的 BCMA 靶向免疫疗法与 GSI 临床研究相结合，以改善患者的预后。