Abstract 2219: Clinical response to immune checkpoint inhibitors in melanoma is associated with distinct gut bacterial species that promote anti-tumor immunity by different mechanisms

Abstract The gut microbiome of cancer patients impacts the response to immune checkpoint inhibitor (CPI) therapy. Using high precision microbiome profiling, we have recently identified 9 diverse species of gut commensal bacteria that are all consistently and strongly associated with CPI response across 4 independent cohorts of melanoma patients. These 9 species represent all 3 of the major phyla in the human intestinal microbiome, and include 4 novel species. A consortium of 9 strains, each representing 1 of these species, is being developed as a live biotherapeutic product (LBP), MB097. In the MCA-205 syngeneic tumor model, MB097 demonstrated synergistic tumor growth inhibition in combination with anti-PD1. The mechanisms by which each of the 9 species exert their anti-tumor effects were investigated, using in vitro assays with primary human immune cells. The bacteria strongly activate dendritic cells (DCs) inducing interleukin (IL)-12. These DCs stimulated by the bacterial strains very potently triggered CD8+ Cytotoxic T Lymphocytes (CTLs) to upregulate Granzyme B and interferon (IFN)γ and kill tumor cells in vitro. Similarly, bacteria-stimulated DCs prompted natural killer (NK) cell activation, as demonstrated by increased expression of IFNγ and elevated capacity for killing tumor cells. DC stimulation by 3 of the 9 strains markedly skewed the cytokine profile to higher IL-12 and lower IL-10, and also led to particularly potent CTL and NK cell activation. These strains represent 3 different families of Firmicutes. Blocking IL-12 reversed the activation and tumor killing effect of DCs stimulated with these strains of Firmicutes. Moreover, the bacterial metabolites derived from 4 different strains triggered CTLs to upregulate the expression of granzyme B and IFNγ and kill tumor cells in vitro. In summary, we have identified 9 gut commensal bacteria as being consistently associated with response to CPI in metastatic melanoma. These bacteria can interact directly with DCs to potently activate CTLs and NK Cells, and some strains of Firmicutes do this via induction of IL-12. Other strains also release metabolites that directly enhance CTL activation. These data begin to identify the different mechanisms by which gut commensal bacteria drive immunotherapy response in human systems. MELODY-1 (NCT06540391) is an ongoing interventional phase 1b study to evaluate MB097 in combination with pembrolizumab in advanced melanoma patients. Citation Format: Matthew James Robinson, Laure Castan, Fernanda Schreiber, Clelia Villemin, Chiara Berlato, David J. Adams, Pippa Corrie, Tim Sharpington, Trevor D. Lawley, Ghaith Bakdash. Clinical response to immune checkpoint inhibitors in melanoma is associated with distinct gut bacterial species that promote anti-tumor immunity by different mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2219.