Core D: Pathology and BioImaging

核心 D：病理学和生物成像

• 批准号: 10362708
• 负责人: CARL D MORRISON
• 金额: $ 45.45万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-03 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362708
• 关键词: Aftercare; Animals; Archives; Biological Assay; Bioluminescence; Biopsy; Blood Vessels; CD3 Antigens; CD8B1 gene; CLIA certified; Cell Communication; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Clonal Expansion; Clonality; Collection; Color; Colorectal; Comprehensive Cancer Center; Computer Assisted; Computers; DNA sequencing; Development; Doctor of Philosophy; Drug or chemical Tissue Distribution; Effector Cell; Ensure; Epitope spreading; Evaluation; Exhibits; FDA approved; Flow Cytometry; Fluorescence Microscopy; Fluorescent in Situ Hybridization; Freezing; Genes; Genomics; Growth; Human; Image; Image Analysis; Image Cytometry; Immune; Immune Response Genes; Immunofluorescence Immunologic; Immunohistochemistry; Immunologics; Immunotherapy; Infrastructure; Ions; Kinetics; Laboratories; Lasers; Magnetic Resonance Imaging; Measures; Microsatellite Instability; Mus; Mutation; Myeloid-derived suppressor cells; New York; Optics; Outcome; Ovarian; PD-1 blockade; PD-1/PD-L1; PTGS2 gene; Pathology; Patients; Pattern; Population; Process; Program Evaluation; Protocols documentation; Recording of previous events; Regimen; Regulatory T-Lymphocyte; Reporting; Reproducibility; Research Personnel; Resource Sharing; Role; Sampling; Scanning; Services; Site; Source; Specimen; System; T cell infiltration; T cell response; T-Lymphocyte; T-cell diversity; Technology; Testing; Tissue Banks; Tissue Procurements; Tissues; Transcript; Tumor Tissue; Universities; Vaccination; Vaccines; Work; bioimaging; chemokine; chemokine receptor; density; design; experimental study; immune checkpoint; immunological intervention; immunological status; in vivo; in vivo imaging; innovation; lymphoid structures; medical schools; melanoma; morphometry; mouse model; multimodality; novel; pathology imaging; preclinical study; programmed cell death ligand 1; programmed cell death protein 1; programs; protein expression; sample collection; sound; tissue culture; transcriptome sequencing; transcriptomics; treatment effect; tumor; tumor growth; tumor microenvironment

ABSTRACT Core D (Pathology and Bio-Imaging Core), directed by Dr. Morrison, MD, will support this clinically oriented Program by providing comprehensive state-of-the-art evaluation of the immune status of tumor microenvironments (TME), using cutting-edge platforms for comprehensive immune profiling, cell and tissue analysis, imaging and image-analysis. Core D includes the following Aims: Aim 1: Provide infrastructure to collect, process, annotate and archive tumor samples and evaluate the immune status of the TME using comprehensive immune profiling. Our Tissue Procurement Service will help collect fresh, frozen and FFPE tumor specimens from the clinical trials of this Program and tissue banking protocols. OmniSeq and multiplex IHC subcore, will perform immunologic, genomic, and transcriptomic assessment of the immune status of the TME, using CLIA-certified Immune Report Card™ (IRC), to determine: 1) transcript levels of 384 immune genes, 2) mutational burden of each tumor, 3) microsatellite instability, and 4) copy number gain of PD-L1 and PD-L2. We will also evaluate 5) on-treatment changes in TCR beta repertoire, to evaluate evidence of tumor-specific T cell response in the TME and 6) Patterns of expression of PD-1/PD-L1/PD-L2 system and COX2 system in relation to T cell infiltrate and clinical outcomes. Aim 2: Provide state-of-the-art immuno-fluorescence imaging and flow cytometry services to interrogate the spatial effects of chemokine modulating agents on immune cell influx, effector- and immuno-suppressive mechanisms in the TME. It will provide state-of-the-art multicolor flow and imaging cytometry, confocal laser scanning and multicolor fluorescence microscopy, combined with computer morphometry and image analysis. Aim 3 (Sub-Core D3): Perform small animal live imaging to determine the kinetics of tumor growth (bioluminescence) in differentially-treated mice and the kinetics of CTL traffic and accumulation in TME. Programmatic Role and Interactions. With Projects 1, 2 and 3 we will evaluate immune profiles of human colorectal, ovarian and melanoma tumors in the course of patient treatment with chemokine-modulating regimens and/or DC vaccines; determine changes in density, clonality and distribution of CTLs and other immune cells in human and mouse tumors treated by CKM in the absence and presence of vaccination and PD-1 blockade, and determine growth kinetics of the differentially treated and non-treated tumors in murine models. We will also determine the impact of treatments on vascular normalization; and formation of tumor- associated lymphoid structures implicated in epitope spreading and long term-treatment effects. Core D will interact with Core A for prioritization of services, with Core B to assure that proper design of studies and sound statistical evaluation of the results. We will work closely with Core C to ensure failsafe procurement of all specimens from the clinical trials, samples annotation and evaluation in context of clinical outcomes.

摘要 由医学博士莫里森指导的核心D（病理学和生物成像核心）将支持这一面向临床的 通过提供全面的最先进的肿瘤免疫状态评估计划 微环境（TME），使用尖端平台进行全面的免疫分析，细胞和组织 分析、成像和图像分析。核心D包括以下目标： 目的1：提供基础设施，以收集、处理、注释和存档肿瘤样本，并评估肿瘤的生物学特性。 使用综合免疫分析确定TME的免疫状态。我们的组织采购服务将 帮助收集本项目临床试验和组织库中的新鲜、冷冻和FFPE肿瘤标本 协议. OmniSeq和多重IHC亚核心将进行免疫学、基因组学和转录组学研究， 使用CLIA认证的免疫报告卡™（IRC）评估TME的免疫状态，以确定： 1)384个免疫基因的转录水平，2）每个肿瘤的突变负荷，3）微卫星不稳定性，以及 4)PD-L1和PD-L2的拷贝数增加。我们还将评估治疗期间TCR β的变化 库，以评估TME中肿瘤特异性T细胞应答的证据，和6）TME的表达模式， PD-1/PD-L1/PD-L2系统和COX 2系统与T细胞浸润和临床结局的关系。 目标2：提供最先进的免疫荧光成像和流式细胞术服务， 趋化因子调节剂对免疫细胞内流、效应细胞和免疫抑制细胞的空间效应 TME中的机制。它将提供最先进的流式细胞仪和成像细胞仪，共聚焦激光 扫描和荧光显微镜，结合计算机形态测量和图像分析。 目标3（子核心D3）：进行小动物活体成像，以确定肿瘤生长的动力学 （生物发光）以及TME中CTL运输和积累的动力学。 方案作用和相互作用。在项目1、2和3中，我们将评估人类的免疫概况， 在用趋化因子调节剂治疗患者的过程中， 方案和/或DC疫苗;确定CTL和其他免疫应答的密度、克隆性和分布的变化。 在不存在和存在疫苗接种的情况下通过CKM处理的人和小鼠肿瘤中的免疫细胞， PD-1阻断，并确定小鼠中差异处理和未处理肿瘤的生长动力学 模型我们还将确定治疗对血管正常化和肿瘤形成的影响- 与表位扩散和长期治疗效应有关的相关淋巴结构。核心D将 与核心A相互作用，确定服务优先次序，与核心B相互作用，确保研究和健全的适当设计 结果的统计评价。我们将与核心C密切合作，以确保所有 来自临床试验的样本、样本注释和临床结局背景下的评价。