PO.CL07.01 · 临床研究
患者主导的多组学纵向研究揭示葡萄膜黑色素瘤进展的新见解
Patient-driven multi-omic longitudinal research study reveals novel insights into uveal melanoma progression
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：在患者参与癌症研究的趋势激增，以及医疗保健领域自我倡导和技术适应的更广泛文化转变的背景下，本研究报告了一项患者合作项目的发现，该项目旨在探究转移性葡萄膜黑色素瘤（UM）进展的机制基础。
方法：患者在PRISM（一项由罕见癌症研究基金会监管的以患者为中心的研究项目）下，依据经IRB批准的方案自愿知情同意。样本采集、处理和分发以进行高级检测的工作，与多个学术治疗中心合作完成，并借助Pattern.org生物物流和生物样本库服务。对2年期间从多个病灶部位采集的样本进行了高级分子诊断检测，包括纵向WES/RNA-seq、蛋白质组学、多重免疫荧光（multiplex IF）染色和类器官药物检测。使用纵向PET/CT成像监测治疗反应，并使用Mint Medical软件对各个病灶进行追踪，同时使用Signatera™无细胞DNA检测进行微小残留病监测。所有临床和研究数据均整合至Pattern.org数据共享库（PDC）以进行下游分析。
结果：该患者表现为转移性UM，初始测序揭示了胚系POT1（Arg363）以及体细胞GNAQ（Q20P）和BAP1（E398，功能缺失）遗传学改变。基于类器官的药物筛选结果未显示对任何靶向治疗选择的明显药物敏感性。患者在接受Pembro/Ipi（帕博利珠单抗/伊匹木单抗）和内源性T细胞疗法期间，疾病稳定且毒性极小，持续6个月。在疾病稳定期间，纵向测序揭示各时间点和多个病灶样本之间遗传学改变一致。在疾病进展时（以肿瘤体积测量值增加和循环肿瘤cfDNA增加为界定），使用WES鉴定出一个新的EZH2（Y641H）变异。对疾病进展前后采集样本的差异变异检出和基因表达分析，凸显了对免疫疗法的潜在耐药机制。此外，使用多重IF染色对肿瘤微环境进行的比较研究，为UM转移和疾病进展的复杂性提供了额外见解。
结论：这项患者主导的研究利用多组学疾病表征和纵向监测，阐明了UM转移中的免疫疗法耐药机制和肿瘤微环境的复杂性。
查看英文原文 English abstract
Introduction: Amid a surging trend in patient engagement in cancer research and the broader cultural shift toward self-advocacy and technology adaptation in healthcare, this study reports findings from a patient-partnered project investigating the mechanistic underpinnings of metastatic uveal melanoma (UM) progression.
Methods: The patient consented voluntarily on IRB-approved protocols under PRISM, a patient-centered research program overseen by The Rare Cancer Research Foundation. Sample collection, processing and distribution for advanced testing was done in collaboration with multiple academic treatment centers and empowered by Pattern.org biologistics and biobanking services. Advanced molecular diagnostic testing was performed on samples collected over a 2 year period from multiple lesion locations, including longitudinal WES/RNA-seq, proteomics, multiplexIF staining, and organoid drug testing. Response to treatment was monitored using longitudinal PET/CT imaging with individual lesion tracking using Mint Medical software, and minimal residual disease monitoring using SignateraTM cell-free DNA testing. All clinical and research data was integrated into the Pattern.org Data Commons (PDC) for downstream analysis.
Results: This patient presented with metastatic UM, initial sequencing revealed germline POT1 (Arg363) and somatic GNAQ (Q20P) and BAP1 (E398, LOF) genetic alterations. Organoid-based drug screening results did not reveal any obvious drug sensitivities to targeted treatment options. The patient experienced disease stabilization with minimal toxicity for 6 months while receiving Pembro/Ipi and an endogenous T Cell therapy. During the course of stable disease, longitudinal sequencing revealed consistent genetic alterations across timepoints and multiple lesion samples. Upon disease progression, defined by increased volumetric measurements in tumor size and increased circulating tumor cfDNA, a new EZH2 (Y641H) variant was identified using WES. Differential variant calling and gene expression analysis collected from samples before and after disease progression highlighted potential resistant mechanisms to immune-based therapies. Further, a comparative study on the tumor microenvironment using multiplex IF staining sheds additional insight into the complexities of UM metastasis and disease progression.
Conclusion: This patient-driven study utilizing multi-omic disease characterization and longitudinal monitoring illuminates immune therapy resistance mechanisms and tumor microenvironment complexities in UM metastasis.
利益披露 Disclosure
A. Smith,
Xilis Stock.
B. Kamphaus,
Noetik Stock.
K. Campbell,
Georgimmune Independent Contractor, Stock.
AME therapeutics Stock.
Geneoscopy LLC Independent Contractor, Stock.
Jaime Leandro Foundation Independent Contractor.
Rare Cancer Research Foundation Independent Contractor.
Noetik Independent Contractor.
Tango Therapeutics Independent Contractor.
Flagship Labs 81 LLC Independent Contractor.
V foundation ).
CRI ).
Parker Institute ).
Melanoma Research Alliance ).
R. Kageyama, None.
B. G. Vincent,
Rare Cancer Research Foundation Independent Contractor, ).
C. Heery,
Arcellx Employment, Stock.
Rare Cancer Research Foundation g., Board of Directors, non-salaried role).
C. N. Spencer,
Coherus Oncology ).
M. Thompson, None.