Translational and Clinical Research Institute, The Medical School, Newcastle University, William Leech Building, Framlington Place, Newcastle upon Tyne, NE4 2HH, UK.
Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
BMC Cancer. 2024 Jun 14;24(1):733. doi: 10.1186/s12885-024-12468-3.
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.
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.
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.
The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).
检查点抑制剂（CPIs）在癌症治疗中被广泛应用，对生存产生了变革性影响。然而，它们以免疫相关不良事件（IrAEs）的形式存在显著的毒性风险，这些不良事件可能持续存在并改变生活。IrAEs 可能需要高剂量和/或延长类固醇的使用，并带来重大的医疗保健负担。它们模仿免疫介导的炎症性疾病（IMIDs），但对其发病机制的理解有限。MEDALLION 项目旨在确定 IrAE 发展中免疫失调的可靶向机制，采用免疫监测方法来确定接受 CPI 治疗但未发生或发生 IrAE 的患者的循环和组织驻留细胞的变化，并同时评估微生物组的贡献。
MEDALLION 是一项非随机纵向队列研究，旨在招募 66 名接受抗 PD1/PD-L1、抗 CTLA-4 或联合治疗的癌症患者。合格的参与者包括辅助或转移性恶性黑色素瘤、间皮瘤和转移性非小细胞肺癌（NSCLC）的患者。在开始 CPI（基线）时以及在随后的 10 个月随访期间的 6 次常规医院就诊时，进行全面的临床评估，同时进行血液、皮肤拭子和粪便取样。保守估计，三分之一的入组患者将经历“显著 IrAE”（SirAE），根据特定于受影响组织/器官系统的预定标准定义。那些发生这种毒性的患者可以选择对受影响的组织进行活检，否则将根据标准护理进行管理。外周血单核细胞将使用多参数流式细胞术进行分析，以研究免疫亚群、其激活状态和细胞因子谱。粪便样本和皮肤拭子将进行 DNA 提取，用于 16S 核糖体 RNA（rRNA）测序和内部转录间隔区（ITS）基因测序，以分别确定细菌和真菌微生物组的多样性，包括与毒性相关的物种。储存的组织活检标本可用于原位和单细胞转录组评估。分析将集中于识别 SirAE 的生物学预测因子和前兆。
通过 MEDALLION 队列评估 IrAEs 的发病机制，有可能开发出用于预测和/或靶向预防或治疗的工具。
该研究于 2023 年 9 月 18 日在 ISRCTN 登记处（43,419,676）注册。
