Project 2

项目2

基本信息

批准号：
10270394
负责人：
Paolo Provenzano
金额：
$ 55.4万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-16 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270394
关键词：
Actins Adhesions Adoptive Immunotherapy Apoptosis Architecture Behavior CD44 gene CRISPR/Cas technology CXC chemokine receptor 3 CXCR3 gene CXCR4 gene Cancer Etiology Cancer Prognosis Cells Cellular immunotherapy Chemicals Clinical Complex Country Coupled Desmoplastic Development Disease Disease Outcome Drug Delivery Systems Dynein ATPase Elements Engineering Environment Extracellular Matrix Flow Cytometry Genes Genome engineering Goals Halofuginone Hyaluronan Image Immune Immunofluorescence Microscopy Immunotherapy In Vitro Infiltration Inflammation Infusion procedures Integrins Intervention Investigation KPC model Longevity Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Measures Mechanics Memory Microtubules Modeling Molecular Motor Myosin ATPase Neoplasm Metastasis Organoids PTK2 gene Pancreatic Ductal Adenocarcinoma Pancreatic carcinoma Phenotype Population Primary Neoplasm RUNX3 gene Radiation therapy Refractory Resistance Sampling Slice Solid Neoplasm Source Survival Rate System T cell therapy T-Lymphocyte Testing Therapeutic Tissues Treatment Efficacy Tumor Antigens Tumor Immunity Tumor Volume Tumor-infiltrating immune cells antigen-specific T cells burden of illness cell motility cellular engineering chemokine chemokine receptor cohort design effector T cell engineered T cells experimental study genetically modified cells genome editing humanized mouse immune checkpoint blockade immunoengineering improved improved outcome in vivo innovation intravital imaging mathematical model migration mortality multiphoton microscopy next generation novel overexpression pancreatic cancer patients pre-clinical preclinical evaluation programs receptor binding response spatiotemporal success targeted treatment transcription factor tumor tumor microenvironment

项目摘要

Pancreatic ductal adenocarcinoma is an extremely lethal disease with the lowest 1-year and 5-year survival rates of any cancer. This is due, in part, to the extremely metastatic behavior of pancreas carcinoma cells and their extreme resistance to both chemical and radiotherapies. Importantly, we now know that a strong, but nevertheless unique, fibrotic and immunosuppressive stromal response is present in PDA. This intense fibroinflammatory, or desmoplastic, response is essentially pathognomonic for PDA and limits infiltration of anti-tumor immune cells and also their ability to move throughout and sample the tumor volume. Indeed, immunotherapies with immune checkpoint blockade or infusion of genetically modified cells are producing remarkable clinical responses in other advanced malignancies, but to date, success has been much more limited in PDA. However, focused preclinical strategies to disrupt the stroma or specifically engineer T cell therapies have shown promise in PDA. Thus, understanding the molecular basis for engineered T cell infiltration and identifying strategies to further enhance their infiltration, migration throughout tumor masses, and persistence and function in cancer will inform cell engineering strategies for improved treatment. Here, we test a number of focused hypotheses using integrated experiments, advanced imaging, and mathematical modeling to elucidate engineered T cell migratory mechanisms both in vivo and in engineered platforms in vitro and utilize genome editing and overexpression to engineer T cells that can maximally infiltrate and move throughout complex tumor microenvironments. We hypothesize that by enhancing the ability of engineered T cells to move throughout tumor we can profoundly improve their efficacy and employ combinations of stroma targeting and T cell therapies to improve disease outcomes. We will dissect mechanisms governing infiltration, longevity and functionality of engineered T cells and determine how engineered T cell migrate within the physically complex tumor environments. This information will be used engineer T cells that most effectively move throughout the entire tumor mass. Using these cells, we will perform rigorous preclinical evaluation of our engineered T cell approach in concert with rational stroma re-engineering. Our goals are aligned with Projects 1 and 3 where we seek to collectively elucidate fundamental mechanisms of immune cell migration and to innovate novel cell engineering approaches to eradicate cancer.

胰腺导管腺癌是一种极其致命的疾病，1年和5年生存率最低任何癌症的发生率。这部分是由于胰腺癌细胞的极端转移行为和它们对化学疗法和放射疗法具有极强的抵抗力。重要的是，我们现在知道，一个强大但然而，PDA 中存在独特的纤维化和免疫抑制基质反应。这种激烈的纤维炎症或促纤维增生反应本质上是 PDA 的特有特征，并限制了 PDA 的浸润。抗肿瘤免疫细胞及其在肿瘤体积中移动和采样的能力。的确，免疫检查点阻断或转基因细胞输注的免疫疗法正在产生在其他晚期恶性肿瘤中取得了显着的临床反应，但迄今为止，成功的程度要大得多仅限于 PDA。然而，重点临床前策略是破坏基质或专门改造 T 细胞疗法在 PDA 中显示出前景。因此，了解工程 T 细胞的分子基础浸润和确定进一步增强其在整个肿瘤块中的浸润和迁移的策略，癌症中的持久性和功能将为改善治疗的细胞工程策略提供信息。在这里，我们使用综合实验、高级成像和数学来测试一些重点假设建模以阐明体内和体外工程平台中的工程化 T 细胞迁移机制并利用基因组编辑和过度表达来改造T细胞，使其能够最大程度地渗透和移动贯穿复杂的肿瘤微环境。我们假设通过增强工程 T 的能力细胞在肿瘤中移动，我们可以极大地提高它们的功效并采用基质组合靶向和 T 细胞疗法可改善疾病结果。我们将剖析控制渗透的机制，工程 T 细胞的寿命和功能，并确定工程 T 细胞如何在体内迁移物理上复杂的肿瘤环境。该信息将用于最有效地设计 T 细胞移动到整个肿瘤块。使用这些细胞，我们将进行严格的临床前评估我们的工程 T 细胞方法与合理的基质重组相结合。我们的目标是一致的项目 1 和 3 我们寻求共同阐明免疫细胞迁移的基本机制并创新新的细胞工程方法来根除癌症。