Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy.

中文翻译：

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抗生素诱导的肠道微生物组代谢输出损失与对 CAR T 细胞疗法的临床反应相关。


抗生素诱导的微生物组失调在肿瘤学中广泛存在，对各种癌症治疗的结果和副作用产生不利影响，包括免疫检查点抑制剂和嵌合抗原受体 T （CAR-T） 细胞疗法。在这项研究中，我们观察到，与其他 ABX 类别相比，先前暴露于具有扩展厌氧覆盖的广谱 ABX，如哌拉西林-他唑巴坦和美罗培南，与大 B 细胞淋巴瘤患者 （n=422） 的抗 CD19 CAR-T 治疗生存结局恶化相关。在这些患者的发现子集 （n=67） 中，我们发现这些 ABX 的使用反过来与肠道微生物组功能的严重生态失调有关，导致肠道和血液代谢组的显着改变，包括微生物效应物，如短链脂肪酸 （SCFA） 和其他阴离子代谢物，这些发现主要在外部验证队列中重现 （n=58）。对循环微生物代谢物的更广泛评估显示，在接受 ABX 治疗的患者中，吲哚和甲酚衍生物以及三甲胺 N-氧化物减少（发现 n=40，验证 n=28）。这些发现在免疫功能正常的 CAR-T 小鼠模型中进行了概括，其中美罗培南诱导的菌群失调导致全身性代谢不良和小鼠抗 CD19 CAR-T 疗效降低。此外，我们证明 SCFA 可以增强 CAR-T 细胞的代谢适应性，从而提高肿瘤杀伤能力。总之，这些结果表明，广谱 ABX 消耗代谢活跃的共生体，其代谢物对增强 CAR-T 疗效至关重要，阐明了 ABX 暴露、微生物组功能及其对 CAR-T 细胞功效影响之间的复杂关系。 这突出了调节微生物组以增强 CAR-T 免疫疗法的潜力。