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: 10907058
• 负责人: Michael H. A. Roehrl
• 金额: $ 20.11万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10907058
• 关键词: 4 year old; Acceleration; 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; Ischemia; 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; Qualifying; Radiation; Research; Sampling; Site; Solid; Specificity; Specimen; Steroids; Temperature; Testing; Time; Tissue Sample; Tissues; Translations; Tumor Tissue; Variant; anti-PD-L1; biobank; cancer type; cell type; clinical practice; cohort; contextual factors; diagnostic assay; gastroesophageal cancer; histological slides; immune checkpoint; immunological status; innovation; malignant breast neoplasm; melanoma; multiplex assay; neoplastic cell; next generation; overtreatment; patient variability; personalized diagnostics; personalized health care; predictive marker; predictive test; preservation; programmed cell death ligand 1; protein expression; sample fixation; tissue fixing; 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.

项目概要/摘要 针对免疫检查点蛋白（例如 PD-L1）的疗法彻底改变了多种疾病的治疗 恶性肿瘤，如恶性黑色素瘤、肺癌、膀胱癌或胃食管癌。 治疗依赖于肿瘤组织中 PD-L1 蛋白表达的预测性生物标志物测定，以识别患有以下疾病的患者： PD-L1 检测很可能会面临两个重大挑战：(i) 它们通常需要在小组织上进行。 肿瘤组织有限的活检，并且 (ii) 免疫组织化学阳性阈值 (1%) 非常小， 强调对最高精确度和分析前样品有效性的关键依赖。 为了解决活检中样本量小且有限的问题，我们开发了一种显色多重检测方法 免疫组织化学检测将 PD-L1 评估与组织和细胞类型特异性标记物相结合，以提供 在单个组织学载玻片上组合诊断和预测测定将 PD-L1 周围的多重测定转移到组织学载玻片上。 临床上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 可以影响 PD-L1 阳性读数的变量吗？关于这些变量的知识非常有限。 重要的是，由于 PD-L1 阳性阈值非常低，需要可靠分离两个非常小的 数字（<1% vs. ≥1%），即使是微小的分析前变量也预计会对 在这方面，组织中的 PD-L1 检测特别需要广泛的表征和控制。 分析前的变异性，甚至比其截止点位于更有利范围内的其他测定法更是如此。 我们的建议基于以下假设：患者特异性因素（例如癌症的分子特征， 目前的免疫状态、既往药物治疗等）和标本相关因素（如活检时机、组织大小、 缺血时间、固定方案等）可以显着影响后续的生物标志物测量。 有了对这些影响的扎实了解，就可以控制和减轻患者特定的和 目标 1：我们将创建一个队列。 我们将利用我们广泛的免疫肿瘤学数据库来测试患者特定背景因素的影响。 目标 2：我们将使用样本相关的分析前变量如何影响检测。 目标 3：一旦我们确定了最佳患者- 特定的和样本相关的程序，我们将在前瞻性免疫治疗队列中验证我们的多重检测 MSKCC 的患者。 意义：该项目将产生有关影响 PD-L1 多重分析的预分析变量的大量数据 这些数据将为最佳样本采集和处理以及策略提供信息。 避免或减少不准确的检测结果创新：这将是第一项系统地探索这两者的研究。 免疫肿瘤学多重免疫组织化学检测中的患者背景因素和样本预分析。 作为我们研究团队的一部分，我们与商业测试开发人员的密切合作将加速 我们将科学发现转化为优化检测，从而使患者直接受益。