PO.CL05.05 · 临床研究
靶向肠道的抗生素调节增强NSCLC的放疗反应,并揭示驱动活体生物治疗药物设计的表观遗传及微生物组驱动的免疫程序
Gut-targeted antibiotic modulation enhances radiotherapy response in NSCLC and uncovers epigenetic and microbiome-driven immune programs enabling live biotherapeutic design
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摘要 Abstract
中文摘要
立体定向体部放疗(SBRT)可诱导免疫原性细胞死亡并激发全身抗肿瘤免疫,但临床反应仍存在异质性。临床前研究表明,肠道微生物组可调节宿主的免疫基调并影响对治疗的反应性。我们此前在肺癌和黑色素瘤模型中证明,口服万古霉素通过清除负责生成短链脂肪酸(SCFAs)及其他免疫抑制性代谢物的革兰阳性菌群,增强放疗的抗肿瘤效应。基于这些观察,我们开展了首个随机临床试点研究,评估在早期非小细胞肺癌(NSCLC)中联合或不联合口服万古霉素的SBRT。符合SBRT条件(50 Gy分4-5次)的患者被随机分配至单用SBRT或SBRT加万古霉素,万古霉素在SBRT前一周及SBRT后五周给药。在五个预先设定的时间点连续采集粪便、血清和PBMC样本。主要终点为可行性和安全性,而免疫激活、无进展生存、总生存以及粪便SCFAs的变化作为探索性终点。共入组17例患者;7例完成万古霉素治疗。未发生≥3级毒性,胃肠道症状为最常见的不良事件。4例患者发生癌症复发,其中3例接受单用SBRT,以淋巴结失败为主要模式。微生物组测序显示特定革兰阳性菌群显著减少,以及万古霉素耐药菌的代偿性扩增。粪便代谢组学显示万古霉素组SCFAs显著下降。PBMC的RNA测序显示抗原加工与提呈通路的稳健富集,以及干扰素相关的免疫激活特征。为拓展这些发现,我们进行了表观遗传及功能验证研究。PBMC染色质分析证实万古霉素治疗受试者在干扰素及抗原提呈相关调控区域的可及性增加。在这些结果的指导下,我们通过将单用SBRT或SBRT+万古霉素患者的粪便移植入经抗生素预处理的小鼠体内,评估万古霉素效应是否可经微生物组转移。定植了万古霉素治疗后人类粪便的小鼠重现了增强的放疗反应,表明这些免疫效应由肠道生态系统介导。这些结果为开发ViRTuE-LTP(增强放疗的活体生物治疗药物)候选物提供了机制依据。与临床观察一致,一个明确定义的三菌株ViRTuE-LTP菌群在补充性小鼠研究中增强了APC激活并增强了放疗反应性。
查看英文原文 English abstract
Stereotactic body radiotherapy (SBRT) can induce immunogenic cell death and stimulate systemic antitumor immunity, yet clinical responses remain heterogeneous. Preclinical studies indicate that the gut microbiome modulates host immune tone and influences responsiveness to therapy. We previously demonstrated in lung cancer and melanoma models that oral vancomycin enhances the antitumor effects of radiotherapy by depleting Gram-positive taxa responsible for generating short-chain fatty acids (SCFAs) and other immunosuppressive metabolites. Based on these observations, we conducted the first randomized clinical pilot study evaluating SBRT with or without oral vancomycin in early-stage non-small cell lung cancer (NSCLC). Patients eligible for SBRT (50 Gy in 4-5 fractions) were randomized to SBRT alone or SBRT plus vancomycin administered for one week before and five weeks after SBRT. Serial stool, serum, and PBMC samples were collected at five predefined time points. Primary endpoints were feasibility and safety, while immune activation; progression-free survival; overall survival; and changes in stool SCFAs served as exploratory endpoints. Seventeen patients enrolled; seven completed vancomycin treatment. No grade ≥3 toxicities occurred, and gastrointestinal symptoms were the most frequent adverse events. Cancer recurrence occurred in four patients, three of whom received SBRT alone, with nodal failure as the predominant pattern. Microbiome sequencing revealed marked reductions in specific Gram-positive taxa and compensatory expansion of vancomycin-resistant organisms. Stool metabolomics demonstrated substantial decreases in SCFAs in the vancomycin arm. RNA sequencing of PBMCs showed robust enrichment of antigen-processing and presentation pathways, together with interferon-related immune activation signatures. To extend these findings, we performed epigenetic and functional validation studies. PBMC chromatin profiling confirmed increased accessibility at interferon- and antigen-presentation-associated regulatory regions in vancomycin-treated subjects. Guided by these results, we evaluated whether the vancomycin effect was microbiome-transferable by engrafting stool from SBRT-alone or SBRT+vancomycin patients into antibiotic-conditioned mice. Mice colonized with post-vancomycin human stool reproduced the enhanced radiotherapy response, demonstrating that the immune effects are mediated by the gut ecosystem. These results provide the mechanistic rationale for developing ViRTuE-LTP (RT-enhancing live biotherapeutic) candidates. Consistent with the clinical observations, a defined 3-strain ViRTuE-LTP consortium enhanced APC activation and potentiated RT responsiveness in complementary murine studies.
利益披露 Disclosure
J. Bradley, None..
A. Facciabene, None.