Enhancing outcomes in medically inoperable early-stage NSCLC with gut-targeted antibiotics and stereotactic body radiotherapy: results from a randomized pilot study.
Steven Joel Feigenberg, Francesca Costabile, Ceylan Tanes, Kyle Bittinger, Roderick O'Connor, Divyansh Agarwal, Giorgos Skoufos, Silavano Salaris, Artemis Hatzigeorgiou, Nektarios Kostopoulos, Shane Lloyd, Cole Friedes, Lisha Chen, Nikhil Yegya-Raman, Keith Cengel, William Levin, Bakir Valentić, Tyler Quarton, Alexander A Shestov, Abigail Berman, Jeffrey Bradley, Amit Maity, Costantinos Koumenis, Edgar Ben-Josef, Andrea Facciabene
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引用次数: 0
Abstract
Background: Gut microbiota modulation is an emerging strategy to improve cancer therapy outcomes. This study evaluated the safety and therapeutic potential of combining oral vancomycin-a non-absorbed, gut-restricted antibiotic with primary activity against gram-positive bacteria-with stereotactic body radiotherapy (SBRT) in early-stage non-small cell lung cancer (NSCLC). The underlying hypothesis was that vancomycin-induced changes in gut microbiota could enhance the antitumor effects of SBRT.
Methods: We conducted a randomized, open-label pilot study in patients with early-stage NSCLC. Patients received oral vancomycin (125 mg, four times daily for 5 weeks, starting 1 week prior to SBRT). Safety, progression-free survival (PFS), overall survival (OS), gut microbiota composition, gut metabolome, and immune responses were evaluated.
Results: The combination of vancomycin and SBRT was well tolerated, with no grade 3 or 4 adverse events reported. Vancomycin treatment selectively depleted certain bacterial strains while enriching others, leading to significant restructuring of the gut microbiota and alterations in the gut metabolome, including reductions in short-chain fatty acids and shifts in other important immunomodulatory metabolites. These changes were associated with dendritic cell and T cell activation, suggesting enhanced systemic immune engagement. Patients receiving vancomycin showed improved outcomes, with a PFS HR of 0.42 (95% CI 0.18 to 0.96; p=0.049) and OS HR of 0.38 (95% CI 0.14 to 0.99; p=0.033), compared with controls.
Conclusions: This pilot study demonstrates that gut microbiome modulation using a gram-positive-targeting, gut-restricted antibiotic in combination with SBRT is safe and may improve clinical outcomes in early-stage NSCLC. These findings support further investigation of targeted microbiome modulation strategies as adjuvants to immunogenic therapies like radiation.
背景：肠道菌群调节是一种改善癌症治疗结果的新兴策略。本研究评估了口服万古霉素（一种主要针对革兰氏阳性细菌的非吸收性肠道限制性抗生素）与立体定向体放疗（SBRT）联合治疗早期非小细胞肺癌（NSCLC）的安全性和治疗潜力。潜在的假设是，万古霉素诱导的肠道微生物群的变化可以增强SBRT的抗肿瘤作用。方法：我们在早期NSCLC患者中进行了一项随机、开放标签的试点研究。患者接受口服万古霉素（125毫克，每天4次，持续5周，开始于SBRT前1周）。评估了安全性、无进展生存期（PFS）、总生存期（OS）、肠道微生物群组成、肠道代谢组和免疫反应。结果：万古霉素联合SBRT耐受性良好，无3级或4级不良事件报道。万古霉素治疗选择性地减少了某些细菌菌株，同时丰富了其他菌株，导致肠道微生物群的重大重组和肠道代谢组的改变，包括短链脂肪酸的减少和其他重要的免疫调节代谢物的改变。这些变化与树突状细胞和T细胞活化有关，表明增强了全身免疫参与。接受万古霉素治疗的患者预后得到改善，PFS HR为0.42 (95% CI 0.18 ~ 0.96；p=0.049)， OS HR为0.38 (95% CI 0.14 ~ 0.99；P =0.033)。结论：这项初步研究表明，使用革兰氏阳性靶向、肠道限制性抗生素联合SBRT进行肠道微生物组调节是安全的，并且可能改善早期NSCLC的临床结果。这些发现支持进一步研究靶向微生物组调节策略作为免疫原性治疗（如放疗）的佐剂。试验注册号：NCT03546829。
期刊介绍：
The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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