The MITRE trial protocol: a study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy

Nicola A Thompson, Grant D Stewart, Sarah J Welsh, Gary J Doherty, Matthew J Robinson, B Anne Neville, Kevin Vervier, Simon R Harris, David J Adams, Katy Dalchau, David Bruce, Nikolaos Demiris, Trevor D Lawley, Pippa G Corrie, Nicola A Thompson, Grant D Stewart, Sarah J Welsh, Gary J Doherty, Matthew J Robinson, B Anne Neville, Kevin Vervier, Simon R Harris, David J Adams, Katy Dalchau, David Bruce, Nikolaos Demiris, Trevor D Lawley, Pippa G Corrie

Abstract

Background: The gut microbiome is implicated as a marker of response to immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types.

Methods: Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome.

Discussion: There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may allow therapeutic manipulation of the microbiome to improve future patient outcomes.

Trial registration: NCT04107168 , ClinicalTrials.gov, registered 09/27/2019. Protocol V3.2 (16/04/2021).

Keywords: Biomarker; Efficacy; Immune checkpoint inhibitor; Immunotherapy; Melanoma; Microbiome; Non-small cell lung cancer; Renal cancer; Toxicity.

Conflict of interest statement

This study has received funding from Microbiotica Ltd.

GDS has received educational grants from Pfizer, AstraZeneca and Intuitive Surgical; consultancy fees from Pfizer, Merck, EUSA Pharma and CMR Surgical; Travel expenses from Pfizer and Speaker fees from Pfizer. BAN is a salaried employee and shareholder in Microbiotica. SH is a salaried employee of Microbiotica. DB is employed by and a shareholder of AstraZeneca. MJR is a salaried employee and shareholder in Microbiotica, as well as a shareholder in AstraZeneca. GJD has received research funding from Roche (institutional); consultancy fees/speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bayer, Merck, MSD, Novartis, Pfizer and Roche. TL is founder and CSO of Microbiotica.

DJA is a paid consultant for Microbiotica and receives research funding from AstraZeneca and OpenTargets. KD is an employee of Astrazeneca. KV is an employee of Microbiotica. DB is a current employee and shareholder of Astrazeneca. PGC has received speaker fees from Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis & Pierre Fabre; advisory board member for BMS and MSD, consultancy fees from Microbiotica. NAT, SJW and ND declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
MITRE Study Flow Chart
Fig. 2
Fig. 2
MITRE Patient Cohorts 1–9

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