Abstract 6671: Harnessing radiation and microbiome modulation for enhanced antitumor immune response in early-stage NSCLC treatment

Abstract In recent years, research has highlighted radiotherapy's (RT) capacity to induce Immunogenic Cell Death (ICD), activating tumor-infiltrating Dendritic Cells (DCs) for cross-presenting tumor-associated antigens (TAAs), leading to robust systemic immune responses. Simultaneously, emerging studies underscore the gut microbiota's crucial role in modulating immunity across diverse human diseases. Our investigation focuses on gut microbiome modulation, specifically using oral Vancomycin, a locally acting antibiotic. This approach enhances the direct and abscopal antitumor effects of RT, evident across multiple cancer models. Findings demonstrate Vancomycin significantly increases CD8+ T cell infiltration, targeting TAAs in primary and abscopal tumors, leading to elevated IFN-β and IFN-γ expression in tumor-derived lymph nodes (TDLNs). Vancomycin's remarkable influence on RT effectiveness directly traces back to its impact on the gut microbiome composition, including a shift from gram-positive to gram-negative bacteria, enrichment of Vancomycin-resistant strains, reduced bacterial diversity, and decreased SCFA concentrations.. Building on these compelling outcomes, we initiated a randomized pilot study involving stage I non-small cell lung cancer (NSCLC) patients undergoing stereotactic body RT (SBRT). Patients were randomized to receive Vancomycin versus placebo, administered at 125 mg four times daily, commencing one week before SBRT and continuing during and after treatment for five total weeks. In an interim analysis, despite a small sample size, significant improvements in Progression-Free Survival (PFS) and Overall Survival (OS) were observed in those receiving the combination therapy. Additional investigations have reaffirmed our earlier findings in mice, emphasizing the depletion of specific bacterial populations, the rise in Vancomycin-resistant strains, and substantial reductions in SCFA concentrations in stool samples. Pathway analysis further underscores the impact of oral Vancomycin on gene expression related to the cross-presentation of TAAs. Together, these findings from both murine and human studies robustly affirm the concept that modulating the gut microbiome with Vancomycin can augment the ability of RT to trigger an anti-cancer immune response. We posit that this pioneering strategy is not only cost-effective but also holds the promise of substantially enhancing patient outcomes. Citation Format: Steven J. Feigenberg, Francesca Costabile, Stefano Pierini, Nektarios Kostopoulos, Renzo Perales-Linares, Mireia Uribe-Herranz, Edgar Ben-Josef, Costa Koumeis, Andrea Facciabene. Harnessing radiation and microbiome modulation for enhanced antitumor immune response in early-stage NSCLC treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6671.