{
  "abstract": "Background Gut microbiota modulation is an emerging strategy to improve cancer therapy outcomes. We recently reported in Journal for ImmunoTherapy of Cancer the results of a randomized, open-label pilot study evaluating oral vancomycin, a non-absorbed, Gram-positive-targeting antibiotic, combined with stereotactic body radiotherapy (SBRT) in early-stage NSCLC.1 The trial demonstrated feasibility, safety, and improved progression-free and overall survival associated with vancomycin-induced shifts in gut microbiota, metabolome, and systemic immune activation. Here, we present new correlative data extending the mechanistic insights of the study.Methods Patients with early-stage NSCLC were randomized to standard SBRT treatment with or without oral vancomycin (125 mg QID × 5 weeks). Clinical outcomes, gut microbiota composition, metabolome, and immune responses were assessed. In parallel, PBMCs collected pre- and post-treatment underwent genome-wide epigenetic profiling. To evaluate functional effects of circulating factors, dendritic cells (DCs) from healthy donors were cultured with patient serum (vancomycin-treated vs control), followed by phenotypic and functional analyses.Results The combination was well tolerated with no Grade 3/4 toxicities. Vancomycin induced selective restructuring of the gut microbiota and metabolome, associated with enhanced DC and T cell activation, and patients in the vancomycin arm showed improved outcomes (PFS HR 0.42, OS HR 0.38). New analyses revealed differential epigenetic modifications in PBMCs from vancomycin-treated patients, particularly at immune-related loci. Ex vivo assays demonstrated that DCs cultured with serum from vancomycin-treated patients exhibited enhanced maturation (CD80/86 upregulation), increased Th1 cytokines secretion, and superior CD8 + T cell activation compared with controls.Conclusions In addition to confirming that gut-restricted antibiotic modulation in combination with SBRT is safe and may improve clinical outcomes in early-stage NSCLC, these new data identify epigenetic reprogramming and functional enhancement of DC activity as novel mechanistic correlates ( figure 1). These findings provide mechanistic insight and support the rationale for microbiome-based strategies to enhance radiotherapy efficacy.Acknowledgements We thank the patients and families who participated in this study. We also acknowledge the Penn Radiation Oncology clinical team for trial coordination, the Abramson Cancer Center Microbiome Program at the University of Pennsylvania for sequencing and analytic support, and Dr. Benjamin Garcia and his laboratory for their expertise and assistance with epigenetic profiling.Trial Registration This trial was registered at ClinicalTrials.gov (Identifier: NCT03546829).Reference Enhancing outcomes in medically inoperable early-stage NSCLC with gut-targeted antibiotics and stereotactic body radiotherapy: results from a randomized pilot study. J Immunother Cancer. 2025 Jul 10;13(7):e011356. doi: 10.1136/jitc-2024-011356Ethics Approval This study was approved by the University of Pennsylvania Institutional Review Board (IRB #822828). All participants provided written informed consent before enrollment and participation in the study, including consent for biospecimen collection and subsequent analyses. All research was conducted in accordance with the Declaration of Helsinki and relevant ethical guidelines.Consent Written informed consent was obtained from all study participants for enrollment in the trial and collection of biospecimens. All data were analyzed in de-identified form. No sensitive or identifiable information is presented in this abstract. A copy of the written consent is available for review by the Editor of this journal.Abstract 1337 Figure 1Gut targeted antibiotic modulation enhance RT efficacy in NSCLC",
  "authors": [
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Steve Feigenberg"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Francesca Costabile"
    },
    {
      "affiliations": [
        "Children’s Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Celyan Tanes"
    },
    {
      "affiliations": [
        "Children’s Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Kyle Bittinger"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Roddy O’Connor"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Divyansh Agarwal"
    },
    {
      "affiliations": [
        "KU Leuven, Leuven, Belgium"
      ],
      "name": "Giorgos Skoufos"
    },
    {
      "affiliations": [
        "Istituto Zooprofilattico Sperimentale delle Venezie, Venezia, Italy"
      ],
      "name": "Silvano Salaris"
    },
    {
      "affiliations": [
        "University of Thessaly, Thessaloniky, Greece"
      ],
      "name": "Artemis Hatzigeorgiou"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Nektarios Kostopoulos"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Lissha Chen"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Bakir Valentic"
    },
    {
      "affiliations": [
        "Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Alexander Shestov"
    },
    {
      "affiliations": [
        "NASA Ames Research Center, Boston, MA, USA"
      ],
      "name": "Tyler Quarton"
    },
    {
      "affiliations": [
        "University of Utah School of Medicine and Huntsman Cancer Institute, Salt Lake City, UT, USA"
      ],
      "name": "Shane Lloyd"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "William Levin"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Nikhil Yegya-Raman"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Keith Cengel"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Cole Friedes"
    },
    {
      "affiliations": [
        "Fox Chase Cancer Center, Philadelphia, PA, USA"
      ],
      "name": "Abigail Berman"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Jeffrey Bradley"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Costantinos Koumenis"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Amit Maity"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Edgar Ben-Josef"
    },
    {
      "affiliations": [
        "Washington University, St. Louis, MO, USA"
      ],
      "name": "Benjamin Garcia"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Andrea Facciabene"
    }
  ],
  "title": "1337 Gut-targeted antibiotic modulation enhances radiotherapy in NSCLC: New epigenetic and dendritic cell functional correlates from a randomized pilot trial",
  "uid": "cc644118-eb4d-509b-ba6f-d3ef2ab04af0"
}