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Interrogating the response of the tumor microenvironment to combination immunotherapy using a microfluidic platform

使用微流控平台探究肿瘤微环境对联合免疫疗法的反应

基本信息

批准号：
10397985
负责人：
ALBERT FOLCH
金额：
$ 52.69万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397985
关键词：
Activation Analysis Address Antibodies Antineoplastic Agents Attention Biological Assay Biopsy CD8-Positive T-Lymphocytes Cancer Biology Cell Communication Cell Death Cells Clinical Trials Colorectal Combination immunotherapy Combined Modality Therapy Complex Computer Analysis Cytotoxic agent Data Development Drug resistance Endothelial Cells Extracellular Matrix Fibroblasts Gene Expression Profiling Glioblastoma Goals Healthcare Human Image Immobilization Immune Immune checkpoint inhibitor Immunomodulators Immunooncology Investigation Knowledge Label Lead Malignant Neoplasms Malignant neoplasm of pancreas Metastatic Neoplasm to the Liver Methods Microfluidics Molecular Molecular Analysis Molecular Target Monoclonal Antibodies Mus Neoplasm Metastasis PD-1/PD-L1 Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phenotype Production Protein Array Proteins Pyroxylin Resources Role Sampling Signal Transduction Signaling Molecule Slice Solid Neoplasm Statistical Models System Systems Biology T-Lymphocyte Technology Testing Time Tissues Transgenic Mice Tumor Tissue Xenograft procedure base biological systems cancer cell cancer imaging cancer therapy checkpoint therapy chemotherapy cytokine design drug action drug discovery drug mechanism drug testing experimental study fighting in vivo innovation insight macrophage migration miniaturize molecular phenotype nano-string neoplastic cell novel therapeutics pancreatic neoplasm preservation protein profiling recruit response small molecule spatiotemporal targeted treatment therapeutically effective tool transcriptomics triple-negative invasive breast carcinoma tumor tumor growth tumor heterogeneity tumor microenvironment tumor-immune system interactions tumorigenesis two photon microscopy two-photon

项目摘要

ABSTRACT The complexity of cell-cell interactions in the tumor represents one of the biggest barriers to understanding cancer and to developing effective therapeutics. Cancer cells constantly interact with fibroblast cells, endothelial cells, immune cells, signaling molecules and the extracellular matrix in the tumor microenvironment (TME). The interactions between host and cancer cells are complex, with effects that may be tumor-suppressive or tumor-promoting. For example, macrophages are first recruited to fight cancer; however, interactions with cancer cells can render them tumor-supportive. Thus, enabling a greater understanding of the complexities of the interaction between cancer cells and their microenvironment can lead to a better understanding of mechanisms of drug resistance, identification of new molecular targets and help address the large unmet needs in treating cancer. Quantitative technologies, such as ours, that integrate ex vivo drug treatments and assess pharmacological responses with cellular and molecular phenotypes in native tissues, should accelerate the discovery and development of novel therapeutics. Yet present tools to study drug responses and the TME have not kept up with drug testing needs. Given the nearly infinite number of potential combinations and limited resources to actually test them, there is a great need for testing platforms that use human, intact tumor tissue ex vivo to predict in vivo responses to combination immunotherapies in miniaturized, multiplexed formats that retain as much of the TME as possible. In our first R01 cycle, we developed a microfluidic platform (called Oncoslice) that allows for selective spatiotemporal exposure of organotypic cultures to dozens of drug conditions, and we demonstrated its utility with cell death assays on xenograft and patient GBM slices. In this second R01 cycle, our goal is to apply our Oncoslice platform to evaluate combination immunotherapies and their interaction with the TME. The platform will be applied to two difficult-to-treat solid tumor types – pancreatic cancer (PCa, mouse, and human) and triple-negative breast cancer (TNBC, mouse). Our recent finding that intratumoral migration of CD8+ T cells is a necessary precursor to anti-tumor activity in response to immune checkpoint inhibitor therapy in pancreatic cancer lends credence to our assertion that developing a micro-scale understanding of cell-cell interactions in the TME is critical. Both PCa and TNBC are extremely heterogeneous and respond poorly to current immune checkpoint inhibitors. New developments to our platform will include live imaging of dynamic changes in the immune TME, tissue and cytokine sampling, selective transcriptomics, and protein pathway profiling. We will integrate phenotypic responses in slices with molecular data to build predictive statistical models. Together, these approaches will establish an innovative platform for immuno-modulatory drug discovery designed to provide insights into the drug's mechanism of action and the TME's role in cancer treatment.

摘要