Saha Satabdi, Rehman Lubna, Rehman Abdur, Darbaniyan Faezeh, Weber Donna M, Becnel Melody, Gaballa Mahmoud, Thomas Sheeba K, Lee Hans C, Chang Chia-Chi, Arora Reetakshi, Menges Meghan, Corallo Salvatore, Davila Marco L, Locke Frederick L, Tanner Mark R, Neelapu Sattva S, Shpall Elizabeth J, Flowers Christopher R, Orlowski Robert Z, Jenq Robert R, Jain Michael D, Peterson Christine, Hansen Doris K, Saini Neeraj Y, Patel Krina K
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.
Blood Adv. 2025 Jul 22;9(14):3429-3440. doi: 10.1182/bloodadvances.2024014476.
Increasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapy. We conducted whole-genome shotgun sequencing on stool samples (N = 117) collected at various times from patients with multiple myeloma (n = 33) who underwent idecabtagene vicleucel (ide-cel) anti-B-cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity after ide-cel infusion, along with significant differences in the bacterial composition linked to therapy response and toxicities. Specifically, we found significant enrichment of Flavonifractor plautii, Bacteroides thetaiotaomicron, Blautia fecis, and Dysosmobacter species in ide-cel responders. A notable finding was the link of major microbiome disruption, defined as the presence of dominant specific taxa (>35% prevalence), and increased facultative pathobionts, like Enterococcus, with ide-cel toxicities, especially cytokine release syndrome (CRS). Patients with genus dominance in baseline samples had a higher incidence of grade 2 or higher CRS at 46.2% than those without genus dominance (11.1%; P = .043). In addition, network analysis and mass spectrometric assessment of stool metabolites revealed important associations and pathways, such as F plautii being linked to increased indole metabolites and pathways in responders. Our findings uncovered novel microbiome associations between ide-cel responses and toxicities that may be useful for developing modalities to improve CAR-T outcomes.
越来越多的证据表明，肠道微生物群可能会影响嵌合抗原受体T细胞（CAR-T）疗法的疗效和毒性。我们对接受idecabtagene vicleucel（ide-cel）抗B细胞成熟抗原CAR-T疗法的多发性骨髓瘤患者（n = 33）在不同时间收集的粪便样本（N = 117）进行了全基因组鸟枪法测序。我们观察到ide-cel输注后细菌多样性显著下降，同时与治疗反应和毒性相关的细菌组成也存在显著差异。具体而言，我们发现ide-cel反应者中Plautii黄酮分解菌、嗜热栖粪杆菌、粪便布劳特氏菌和异味杆菌属显著富集。一个值得注意的发现是，主要微生物群破坏（定义为存在优势特定分类群，患病率>35%）以及兼性致病共生菌（如肠球菌）的增加与ide-cel毒性相关，尤其是细胞因子释放综合征（CRS）。基线样本中存在属优势的患者2级或更高CRS的发生率为46.2%，高于无属优势的患者（11.1%；P = .043）。此外，粪便代谢物的网络分析和质谱评估揭示了重要的关联和途径，例如Plautii菌与反应者中吲哚代谢物和途径的增加有关。我们的研究结果揭示了ide-cel反应和毒性之间新的微生物群关联，这可能有助于开发改善CAR-T治疗效果的方法。
