“Immune System Modulation with Oral Vancomycin in combination with Stereotactic Body Radiotherapy (SBRT) for medically inoperable Early-Stage Non-small Cell Lung Cancer”
Authors: Feigenberg Steven J. , Costabile Francesca , Tanes Ceylan , Bittinger Kyle , O’Connor Roddy , Agarwal Divyansh , Skoufos Giorgos , Salaris Silvano , Hatzigeorgiou Artemis , Kostopoulos Nektarios , Lloyd Shane , Friedes Cole , Chen Lisha , Yegya-Raman Nikhil , Cengel Keith , Levin William , Valentić Bakir , Quarton Tyler , Shestov Alexander A. , Berman Abigail , Bradley Jeffrey , Maity Amit , Koumenis Costantinos , Ben-Josef Edgar , Facciabene Andrea 
Published: January 2025

AbstractWe present the results of a randomized, open-label pilot study investigating the combination of oral vancomycin and stereotactic body radiotherapy (SBRT) in early-stage non-small cell lung cancer (NSCLC). Our findings highlight vancomycin’s safety, evidenced by the absence of Grade 3 or 4 adverse events, and its potential to enhance the antitumor efficacy of SBRT. The observed enhancement is linked to vancomycin’s modulation of the gut microbiota, which triggers significant metabolic changes and immune activation, thereby contributing to improved progression-free survival (PFS) and overall survival (OS). Patients received vancomycin (125 mg, four times daily for five weeks, starting one week prior to SBRT), which induced restructuring of the gut microbiome and significant changes in the gut metabolome. Key changes included reductions in short-chain fatty acids (SCFAs) and shifts in other immunomodulatory metabolites. These metabolic shifts were associated with the activation of dendritic cells and T cells, creating a pro-inflammatory environment conducive to strengthening SBRT’s antitumor efficacy. The combination of vancomycin and SBRT presents a novel, low-toxicity therapeutic approach for early-stage NSCLC, showing promising initial outcomes. While the results are encouraging, further research with larger cohorts is necessary to verify these findings and elucidate the underlying mechanisms that contribute to the observed clinical benefits.WHAT IS ALREADY KNOWN ON THIS TOPICRadiation therapy is a primary treatment for early-stage non-small cell lung cancer and offers excellent local control in early-stage NSCLC, the challenges of regional and distant failures which occur in up to 50% of patients, lead to increased morbidity and mortality. The gut microbiome is increasingly recognized in cancer immunotherapy. RT can induce Immunogenic Cell Death, activating the immune system and promoting abscopal effect to impact untreated lesions. Our previous preclinical studies have shown that antibiotics like vancomycin can modulate these immune effects and enhance RT’s antitumor activity.WHAT THIS STUDY ADDSThis clinical study corroborates our previous preclinical findings by demonstrating the safety of vancomycin and its potential to enhance the antitumor effects of RT, despite the small cohort size. These findings suggest that vancomycin could be strategically used to improve RT outcomes.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYOur findings prompt further investigation into this combined treatment in a larger patient cohort to confirm enhanced progression-free survival and overall survival. Exploring the impact on distal recurrences and applying this strategy to more advanced patient stages could significantly influence future research directions and clinical practices. This approach may also guide policy towards integrating microbiome modulation strategies in standard cancer treatment protocols.