Identification of a microbiome signature predicting immune checkpoint inhibitor outcomes across multiple cancer types: the MITRE study


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Pippa Corrie1, Sarah Welsh2, Grant Stewart2, Gary Doherty3, Kevin Vervier4, Anne Neville4, Christine Parkinson3, Kate Fife3, Guy Faust5, Kamalram Thippu Jayaprakash4, Thomas Geldart6, Ewan Brown7, Matthew Wheater8, Jenny Nobes9, Tania Tillett10, Toby Talbot11, Clare Barlow12, Helen Winter4, David Bruce3, Katy Dalchau3, Nikos Demiris3, David Adams13, Mat Robinson4, Trevor Lawley4
1Addenbrooke’s Hospital, 2University of Cambridge, 3Cambridge University Hospitals NHS Foundation Trust, 4Other, 5University Hospitals of Leicester NHS Trust, 6Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, 7Western General Hospital, 8University Hospital Southampton NHS Foundation Trust, 9Norfolk & Norwich University Hospitals NHS Foundation Trust, 10Royal United Hospitals Bath NHS Foundation Trust, 11Royal Cornwall Hospitals NHS Trust, 12Somerset NHS Foundation Trust, 13Wellcome Sanger Institute

Abstract

Background

Preliminary preclinical and clinical research implicate the gut microbiome as a biomarker of response to immune checkpoint inhibitors (ICIs). So far, identification of specific responsible bacterial taxa has been inconsistent between published studies, which limits future application. By culturing and metagenomic sequencing of stool sample bacteria, our group has identified a unique microbiome signature, which may predict response to ICIs across all key published series as well as our own melanoma patient series (Robinson M et al, J Immunother Cancer 2020;8(suppl 3):A404). Because the patient numbers in all published series remain low, we are now further exploring and validating this microbiome signature in a larger scale study across several different cancer types.

Method

MITRE (Microbiome Immunotherapy Toxicity and Response Evaluation) is a UK NIHR portfolio multi-centre prospective study funded jointly by Cancer Research UK and Microbiotica Ltd (NCT04107168). Up to 1800 patients receiving ICIs will be recruited over a 5-year period. In the first stage, 300 patients with advanced melanoma (cohort 1:anti-PD1 monotherapy, cohort 2:anti-PD1+anti-CTLA-4 combination), renal cancer (cohort 3:anti-PD(L)1+kinase inhibitor, cohort 4:anti-PD1+anti-CTLA-4 combination) and non-small cell lung cancer (cohort 5:anti-PD(L)1 monotherapy, cohort 6:anti-PD(L)1+chemotherapy+anti-angiogenic) are being recruited, 50 patients to each cohort. A cohort-specific, simulation-based power calculation will then be performed, guiding subsequent recruitment. 

Stool and blood are collected prior to treatment, at 3, 6 and 12 months, or disease progression (whichever is sooner), as well as after any grade >3 immune-related adverse events. Patients collect and freeze their own stool samples which are cultured and subjected to shotgun metagenomic sequencing. Plasma, whole blood, buffy coat, RNA and PBMCs are being stored, for correlative studies. Any tumour, or organ biopsies taken prior to and during treatment are also being collected. Clinical data collection includes treatment, disease response (using RECIST criteria) and toxicity. The primary outcome measure is 1 year progression-free survival. Patients are also asked to invite a household member to be part of the study control group.

As of June 2021, 8 sites have opened, 43 patients and 8 household controls have been recruited.

Results


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Impact statement