Abstract 1783: Precision microbiome profiling identifies a novel biomarker predictive of Immune Checkpoint Inhibitor response in multiple cohorts and a potent therapeutic consortium of bacteria

Four independent international groups have demonstrated that the pre-treatment gut microbiome of cancer patients is associated with the subsequent response to treatment with Immune Checkpoint Inhibitors (ICI) [1-4]. However, each study identified different bacteria as being linked to outcome, which has limited the development of drug response biomarkers and novel microbiome-based therapeutics. Here we describe the identification of a microbial signature predictive of response to ICI across multiple melanoma studies, and a derived Live Bacterial Therapeutic with potent anti-tumour activity. MELRESIST is a single centre, prospective melanoma patient data and biosample collection research study. We collected longitudinal stool samples from 69 patients with advanced melanoma who received standard anti-PD-1+/- anti-CTLA-4 antibodies. Shotgun metagenomic sequencing analysis of the baseline stool microbiome was done using Microbiotica9s platform, which comprises the world9s leading Reference Genome Database to give the most comprehensive and precise mapping of gut microbiomes. Using 6 months progression-free survival as our cut-off for response, the analysis revealed a small but discrete microbiome signature that differentiated responders and non-responders with an accuracy of 93%. We extended this signature by reanalysing another 3 melanoma patient stool sample sequence datasets [1-3] using the Microbiotica platform, and a machine learning-based bioinformatic model. The resultant bacterial signature accurately predicted response when all 4 studies when combined (91%), as well as when the cohorts were analysed individually (82-100%). We validated the model using independent cohorts and the signature using NSCLC and Renal Cell Carcinoma (RCC) datasets [4]. The latter indicated the bacteria associated with response may differ slightly between indications. At the core of the signature was 9 bacteria that were all overrepresented in patients that responded to ICI treatment. Notably as a consortium, these 9 bacteria demonstrated tumor growth inhibition when dosed in a syngeneic mouse model. These strains also stimulate primary immune cells in vitro leading to tumor cell killing. In summary, we have identified a microbiome biomarker that is predictive of response to ICI treatment in multiple clinical studies from different countries. In addition, a unique set of bacteria derived from the signature has great therapeutic potential in combination 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, Roy Rabbie, Doreen Milne, Catherine Booth, Christine Parkinson, Sarah J. Welsh, David Bruce, Emily Barker, David Adams, Pippa Corrie, Trevor D. Lawley. Precision microbiome profiling identifies a novel biomarker predictive of Immune Checkpoint Inhibitor response in multiple cohorts and a potent therapeutic consortium of bacteria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1783.