Abstract P074: MB097: A therapeutic consortium of bacteria clinically-defined by precision microbiome profiling of immune checkpoint inhibitor patients with potent anti-tumor efficacy in vitro and in vivo

Abstract

Abstract Independent groups have demonstrated that the pre-treatment gut microbiome of cancer patients impacts the subsequent response to Immune Checkpoint Inhibitor (ICIs) therapy [1-4]. However, each study identified different sets of bacteria linked to outcome, which has limited the development of drug response biomarkers and clinic-first design of novel microbiome-based therapeutics. The Cambridge (UK) MELRESIST study includes a cohort of advanced melanoma patients receiving approved ICIs. Pre-treatment stool samples from MELRESIST were analysed by Microbiotica using shotgun metagenomic sequencing. Microbiotica's platform comprises the leading Reference Genome Database to give the most comprehensive and precise mapping of the gut microbiome. A bioinformatic analysis identify a small discrete microbiome signature that was different between responders and non-responders. We extended this signature by reanalysing three published melanoma cohorts [1-3] using the Microbiotica platform. The resultant bacterial signature predicted whether or not a patient responded to anti-PD1-based therapy with an accuracy of 91% in all four studies combined and was also an effective biomarker for each cohort individually. We validated the signature using a NSCLC study [4] indicating that it has great potential as a clinical biomarker for a number of indications. The signature was strongly skewed towards species raised in abundance in responding patients, suggesting that the microbiome influences ICI treatment primarily through bacteria that enhance the efficacy of the drugs. At the core of the signature was nine species strongly associated a positive outcome, which we hypothesized to be a central driver of drug response. MB097 is a consortium comprised of all nine bacteria. In a syngeneic mouse model of cancer, MB097 was able inhibit tumor growth, but most strikingly was potently synergistic when dose with anti-PD1. To understand the mechanisms by which these bacteria drive an anti-tumor response, we have profiled the bacteria individually and as a consortium in multiple assays with primary human immune cells. The bacteria strongly activate dendritic cells with a number inducing high levels of IL-12 relative to IL-10. These bacteria-stimulated dendritic cells went on to trigger Cytotoxic T Lymphocytes (CTLs) to upregulate Granzyme B, Perforin and IFNg. Further, we have demonstrated that these primed CTLs are very effective at tumor cell killing in vitro. In summary, Microbiotica's precision microbiome profiling and the MELRESIST study has allowed us to identify a consortium of bacteria, MB097, strongly linked to response in multiple melanoma cohorts and a NSCLC study. The consortium drives immune-mediated tumor killing in vivo and in vitro. MB097 is being scaled up for manufacture as a novel co-therapy with ICIs. References 1 Matson V et al Science (2018) 359:104 2 Gopalakrishnan V Science (2018) 359:97 3 Frankel AE et al Neoplasia (2017) 19:848 4 Routy B et al Science (2018) 359:91 Citation Format: Matthew J. Robinson, Kevin Vervier, Simon Harris, Amy Popple, Dominika Klisko, Robyne Hudson, Ghaith Bakdash, Laure Castan, Clelia Villemin, David J. Adams, Doreen Milne, Catherine Booth, Christine Parkinson, Roy Rabbie, Sarah J. Welsh, Emily Barker, Katie Dalchau, Pippa Corrie, Trevor Lawley. MB097: A therapeutic consortium of bacteria clinically-defined by precision microbiome profiling of immune checkpoint inhibitor patients with potent anti-tumor efficacy in vitro and in vivo [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P074.