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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.
CONCLUSIONS: 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.
BACKGROUND: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).
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.
CONCLUSIONS: 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.
BACKGROUND: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).
摘要：
背景：检查点抑制剂（CPIs）广泛用于癌症治疗，对生存有变革性影响。尽管如此，它们还是以免疫相关不良事件（IrAEs）的形式存在重大的毒性风险，这可能是持续的和改变生活的。IrAE可能需要高剂量和/或长时间的类固醇使用，并且代表了重大的医疗保健负担。它们模拟免疫介导的炎性疾病（IMID），但对其发病机理的了解有限。MEDALLION项目旨在确定IrAE发育中免疫失调的靶向机制，采用免疫监测方法来确定有/没有发展的CPI接受者的循环和组织驻留细胞的变化，并平行评估微生物组的贡献。
方法：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。符合条件的参与者包括在辅助或转移环境中患有恶性黑色素瘤的参与者，在转移环境中治疗的间皮瘤和非小细胞肺癌（NSCLC）。综合临床评估是与血液一起进行的，在CPI开始时(基线)和随后的常规住院期间,在10个月的随访期内进行6次皮肤拭子和粪便采样.保守地预计，三分之一的登记患者将经历“显著IrAE”（SirAE），根据特定于受影响的组织/器官系统的预定标准定义。那些产生这种毒性的人可以任选地在适当的情况下对受影响的组织进行活检，否则根据护理标准进行管理。外周血单核细胞将使用多参数流式细胞术分析免疫亚群，它们的激活状态和细胞因子谱。粪便样本和皮肤拭子将进行16S核糖体RNA（rRNA）测序和内部转录间隔区（ITS）基因测序的DNA提取，以确定细菌和真菌微生物组的多样性，分别,包括与毒性有关的物种。储存的组织活检可用于原位和单细胞转录组评估。分析将侧重于识别SirAE的生物预测因子和前体。
结论：IrAE的发病机制将通过MEDALLION队列进行评估，有潜力开发用于预测的工具和/或有针对性的预防或治疗的策略。
背景：该研究于2023年9月18日在ISRCTN注册表中注册（43,419,676）。
方法：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。符合条件的参与者包括在辅助或转移环境中患有恶性黑色素瘤的参与者，在转移环境中治疗的间皮瘤和非小细胞肺癌（NSCLC）。综合临床评估是与血液一起进行的，在CPI开始时(基线)和随后的常规住院期间,在10个月的随访期内进行6次皮肤拭子和粪便采样.保守地预计，三分之一的登记患者将经历“显著IrAE”（SirAE），根据特定于受影响的组织/器官系统的预定标准定义。那些产生这种毒性的人可以任选地在适当的情况下对受影响的组织进行活检，否则根据护理标准进行管理。外周血单核细胞将使用多参数流式细胞术分析免疫亚群，它们的激活状态和细胞因子谱。粪便样本和皮肤拭子将进行16S核糖体RNA（rRNA）测序和内部转录间隔区（ITS）基因测序的DNA提取，以确定细菌和真菌微生物组的多样性，分别,包括与毒性有关的物种。储存的组织活检可用于原位和单细胞转录组评估。分析将侧重于识别SirAE的生物预测因子和前体。
结论：IrAE的发病机制将通过MEDALLION队列进行评估，有潜力开发用于预测的工具和/或有针对性的预防或治疗的策略。
背景：该研究于2023年9月18日在ISRCTN注册表中注册（43,419,676）。
