Evaluation of Patient Factors and Sample Pre-Analytics on Predictive Multiplex Immunohistochemical Assays in Immuno-Oncology Patients

免疫肿瘤患者预测多重免疫组织化学分析的患者因素和样品预分析的评估

• 批准号: 10451186
• 负责人: Michael H. A. Roehrl
• 金额: $ 20.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451186
• 关键词: 4 year old; Address; Affect; Age; Alcohols; Antiemetics; Asian; Biological Assay; Biological Markers; Biopsy; Black race; Body mass index; Cancer Patient; Categories; Characteristics; Clinic; Clinical; Collaborations; Cytotoxic Chemotherapy; Data; Databases; Dependence; Eastern Cooperative Oncology Group; Ensure; Ethnic Origin; Evaluation; Excision; Face; Formalin; Freezing; Gender; Goals; Guidelines; Health Care Costs; Hispanic; Ice; Immunohistochemistry; Immunooncology; Immunotherapy; Knowledge; Length; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Measurement; Measures; Memorial Sloan-Kettering Cancer Center; Molecular; Non-Small-Cell Lung Carcinoma; Outcome; Paraffin Tissue; Patients; Performance; Performance Status; Pharmacotherapy; Physiological; Procedures; Process; Prospective Studies; Prospective cohort; Proteins; Protocols documentation; Radiation; Research; Sampling; Sensitivity and Specificity; Site; Solid; Specimen; Steroids; Temperature; Testing; Time; Tissue Sample; Tissues; Translations; Tumor Tissue; Variant; anti-PD-L1; base; biobank; cancer type; cell type; clinical practice; cohort; diagnostic assay; gastroesophageal cancer; histological slides; immune checkpoint; immunological status; innovation; malignant breast neoplasm; melanoma; multiplex assay; neoplastic cell; next generation; overtreatment; personalized diagnostics; personalized health care; predictive marker; predictive test; preservation; programmed cell death ligand 1; protein expression; sample fixation; tumor

Project Summary/Abstract Therapies against immunologic checkpoint proteins, such as PD-L1, have revolutionized the treatment of multiple malignancies, such as malignant melanoma, lung cancer, bladder cancer, or gastroesophageal cancer. All of these therapies depend on predictive biomarker assays for PD-L1 protein expression in tumor tissue to identify patients who will most likely respond. PD-L1 assays face two significant challenges: (i) they often need to be performed on small tissue biopsies where tumor tissue is limited and (ii) the threshold for positivity by immunohistochemistry (1%) is very small, highlighting crucial dependence on utmost precision and pre-analytical sample validity. To address the issue of small and limited samples in biopsies, we have developed a chromogenic multiplexed immunohistochemical assay that combines PD-L1 assessment with tissue and cell type-specific markers to provide a combined diagnostic and predictive assay on a single histologic slide. To move multiplexed assays around PD-L1 into the clinic, there exists an important knowledge gap: what are the patient-specific factors and specimen-related pre-analytical variables that can influence the readout of PD-L1 positivity? Very limited knowledge is available about these variables. Importantly, because the PD-L1 positivity threshold is so low and requires the reliable separation of two very small numbers (<1% vs. ≥1%), even minute pre-analytical variabilities would be expected to have significant negative impact on assay validity. In that respect, PD-L1 testing in tissue is particularly in need of extensive characterization and control of pre-analytical variability, even more so than other assays whose cut-off points lie in more favorable ranges. Our proposal is based on the hypothesis that both patient-specific factors (such as molecular features of the cancer, current immune status, prior drug therapy, etc.) and specimen-related factors (such as timing of biopsy, size of tissue, ischemic time, fixation protocol, etc.) can significantly influence subsequent biomarker measurements. We further hypothesize that solid knowledge about these influences will allow controlling for and mitigating patient-specific and specimen-related effects and will lead to more accurate and valid biomarker assessment. Aim 1: We will create a cohort to test the influence of patient-specific context factors. We will make use of our extensive immuno-oncology database and biobank of >5,000 patients. Aim 2: We will test how specimen-related pre-analytical variables affect the assay using a wide variety of fresh, frozen, and formalin fixed tissue types and sizes. Aim 3: Once we have defined optimal patient- specific and specimen-related procedures, we will validate our multiplex assay in a prospective cohort of immunotherapy patients at MSKCC. Significance: This project will yield abundant data about the pre-analytical variables that influence a PD-L1 multiplex immunohistochemistry assay. These data will inform optimal specimen acquisition and handling and strategies for avoiding or mitigating inaccurate assay results. Innovation: This will be the first study to systematically explore both patient context factors and specimen pre-analytics in multiplexed immunohistochemical testing for immuno-oncology. Our close collaboration with commercial test developers as part of our research team will accelerate the translation of our scientific findings into optimized assays for the direct benefit of patients.

项目摘要/摘要 针对免疫学检查点蛋白（例如PD-L1）的疗法已彻底改变了多种的治疗 恶性肿瘤，例如恶性黑色素瘤，肺癌，膀胱癌或胃食管癌。所有这些 疗法依赖于肿瘤组织中PD-L1蛋白表达的预测性生物标志物测定，以鉴定患者 很可能会做出回应。 PD-L1阿萨斯面临两个重大挑战：（i）通常需要在小组织上进行它们 肿瘤组织受到限制和（ii）免疫组织化学阳性阈值的活检（1％）很小， 强调至关重要的精度和分析前样品有效性的关键依赖性。 为了解决活检中的小和有限样本的问题，我们已经开发了一个成色的多路复用 将PD-L1评估与组织和细胞类型特异性标记相结合的免疫组织化学测定法 单个组织学幻灯片上的诊断和预测测定。将PD-L1周围的多路复用测定移动到 诊所，存在一个重要的知识差距：患者特异性因素和标本相关的预分析是什么 会影响PD-L1潜力读数的变量？有关这些变量的知识非常有限。 重要的是，因为PD-L1正阈值太低，需要可靠的两个非常小的分离 数字（<1％vs.≥1％），即使是分析前的分析差异，也有望对 测定有效性。在这方面，组织中的PD-L1测试尤其需要广泛的表征和控制 分析前的可变性，甚至比其他截止点更有利的范围的其他测定法更大。 我们的建议基于以下假设：两个患者特异性因素（例如癌症的分子特征， 当前的免疫学状况，先前的药物治疗等）和标本相关因素（例如活检的时间，组织的大小， 缺血时间，固定方案等）可以显着影响随后的生物标志物测量。我们进一步 假设对这些影响的扎实知识将允许控制并减轻患者特异性和 标本相关的效果，并将导致更准确和有效的生物标志物评估。目标1：我们将创建一个队列 测试患者特定环境因素的影响。我们将利用我们广泛的免疫肿瘤数据库 和> 5,000名患者的生物库。 AIM 2：我们将测试使用标本相关的预分析变量如何使用使用 目标3：一旦我们定义了最佳患者 - 特定和标本相关的程序，我们将在预期的免疫疗法中验证我们的多重测定 MSKCC的患者。 意义：该项目将产生有关影响PD-L1多路复用的预先分析变量的大量数据 免疫组织化学测定法。这些数据将为最佳标本获取和处理和处理和策略提供信息 避免或减轻不准确的评估结果。创新：这将是系统探索两者的首次研究 免疫肿瘤学多重免疫组织化学测试中的患者上下文因素和标本预分析。 作为研究团队的一部分，我们与商业测试开发人员的密切合作将加速 我们的科学发现是为患者直接益处的优化测定法。