Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study

Our plain-English summary of Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study, by A. Gault, L. Hogarth, K.C. Williams, et al (BMC Cancer, 2024).

The study

• Authors: A. Gault, L. Hogarth, K.C. Williams, A. Greystoke, N. Rajan, A. Speight, C.A. Lamb, A. Bridgewood, L.J. Brown-Schofield, F. Rayner, J.D. Isaacs, J. Nsengimana, C.J. Stewart, A.E. Anderson, R. Plummer, A.G. Pratt
• Journal: BMC Cancer
• Published: 2024;24(1):733
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel.

Methods: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a "significant IrAE" (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs.

Discussion: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment.

Trial Registration: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

© 2024. The Author(s).

In plain English

This article was a study protocol. It described a planned study and reported no results. The study, called MEDALLION, was designed as a single-centre observational cohort in Newcastle upon Tyne, UK. It aimed to recruit about 70 adults, with about 66 expected to complete it, who were starting cancer immunotherapy drugs called checkpoint inhibitors. Eligible patients had malignant melanoma, non-small cell lung cancer, or mesothelioma. The article did not study asbestos exposure, and mesothelioma patients were one of three eligible cancer groups. Blood, skin swabs and optional stool samples were to be collected at six scheduled visits in total, starting at baseline, for up to 10 months or until a significant side effect, with swabs and stool limited to the first 53 evaluable participants. The main clinical endpoint was a 'significant' immune-related side effect, defined by organ-specific criteria. The main planned analysis would test whether a marker in blood immune cells (pSTAT3 in CD4+ T cells) predicts these side effects. The authors stated that the study's single-centre design means its findings may not apply to more diverse populations.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Study protocol for a planned non-randomised, prospective, longitudinal observational cohort study (no results reported)
• Who was studied: Planned: approximately 70 adult patients (about 66 expected to complete) with malignant melanoma, non-small cell lung carcinoma (NSCLC) or mesothelioma starting checkpoint inhibitor treatment at the Northern Centre for Cancer Care, Newcastle upon Tyne, UK
• Exposure: Checkpoint inhibitor cancer immunotherapy: combination ipilimumab and nivolumab, or single-agent nivolumab, pembrolizumab or atezolizumab. Asbestos exposure was not studied.
• The authors' conclusion: The authors stated that the cohort will be used to assess how immune-related side effects of checkpoint inhibitors develop, with the potential to develop tools to predict them or strategies to prevent or treat them.
• Limitations the authors state:
  • Because the study is run at a single centre, the authors stated that its findings may not apply to geographically and demographically diverse populations.
  • The authors acknowledged that dividing diverse immune-related side effects into 'significant' and 'non-significant' on clinical grounds is partly arbitrary.

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Cohort Study, checkpoint inhibitors, Immune-Related Adverse Events, PD-L1, CTLA-4, Mesothelioma, Carcinoma.

Related studies

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• Registry study of immune-related adverse events using electronic patient-reported outcome in patients with cancer receiving immune checkpoint inhibitors: protocol for a multicentre cohort study — T. Hirata, T. Kawaguchi, et al. (2023)
• Immune Checkpoint Inhibition for Unresectable Malignant Pleural Mesothelioma — W. Cui, S. Popat (2021)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)
• Efficacy of Immune Checkpoint Inhibitors in Rare Tumours: A Systematic Review — F. Petrelli, F. Consoli, et al. (2021)
• Checkpoint-checkpoint combinations in cancer: from mechanistic rationale to translational impact — A. Mazzocca, S. Calagna, et al. (2026)

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