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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具致命性的疾病，其1年和5年生存率最低