嵌合抗原受体 (CAR) T 细胞和针对 B 细胞成熟抗原 (BCMA) 的双特异性抗体 (BsAb) 显着推进了复发性和难治性多发性骨髓瘤 (MM) 的治疗。尽管如此，对 BCMA 靶向疗法的耐药性仍然是一个重大挑战。 γ-分泌酶导致的 BCMA 脱落是一种已知的耐药机制，临床前研究表明抑制可能会改善抗 BCMA 治疗。利用 γ 分泌酶抑制剂 (GSI)、crenigacestat 和抗 BCMA CAR T 细胞 (FCARH143) 的 I 期临床试验，我们利用单核 RNA 测序和转座酶可及染色质 (ATAC) 测序来表征GSI对肿瘤微环境的影响。 GSI 最显着的影响涉及对单核细胞的影响，已知单核细胞可促进肿瘤生长。除了观察到非经典单核细胞频率的减少外，我们还检测到暴露于 GSI 后基因表达、染色质可及性和推断的细胞间相互作用的显着变化。尽管许多表达改变的基因与 γ 分泌酶依赖性信号传导相关，例如 Notch，但其他途径也受到影响，表明 GSI 具有深远的影响。最后，我们在一些先前接受过抗 BCMA 治疗的患者中检测到 BCMA 位点的单等位基因缺失，这与无进展生存期缩短显着相关（中位 PFS 为 57 天与 861 天）。 GSI 正在与全谱 BCMA 靶向药物结合进行探索，我们的结果揭示了 GSI 对肿瘤和免疫细胞群的广泛影响，为增强 BCMA 导向疗法的机制提供了见解。版权所有 © 2024 美国血液学会。

Chimeric antigen receptor (CAR) T-cells and bispecific antibodies (BsAb) targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma (MM). Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by gamma-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase I clinical trial of the gamma-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T-cells (FCARH143), we utilized single-nuclei RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which are known to promote tumor growth. In addition to observing a reduction in the frequency of non-classical monocytes, we also detected significant changes in gene expression, chromatin accessibility, and inferred cell-cell interactions following exposure to GSI. Although many genes with altered expression are associated with gamma-secretase-dependent signaling, such as Notch, other pathways were affected, indicating GSI has far-reaching effects. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (median PFS 57 days versus 861 days). GSIs are being explored in combination with the full spectrum of BCMA targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies.Copyright © 2024 American Society of Hematology.