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：
10633090
负责人：
ALBERT FOLCH
金额：
$ 52.74万
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/10633090
关键词：
Acceleration 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 Immunooncology Invaded Investigation Label Macrophage 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 Pharmacotherapy Phase Phenotype Production Protein Array Proteins Pyroxylin Resources Role Sampling Signaling Molecule Slice Solid Neoplasm Statistical Models System Systems Biology T-Lymphocyte Technology Testing Time Tissues Transgenic Mice Tumor Promotion Tumor Tissue Xenograft procedure biological systems cancer cell cancer imaging cancer therapy checkpoint therapy chemotherapy cytokine design drug action drug discovery drug mechanism drug testing experimental study fighting immune modulating agents immunomodulatory therapies in vivo innovation insight knowledge integration migration miniaturize molecular phenotype nano-string neoplastic cell novel therapeutics pancreatic neoplasm pharmacologic 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.

抽象的肿瘤中细胞间相互作用的复杂性是理解的最大障碍之一癌症并开发有效的治疗方法。癌细胞不断与成纤维细胞、内皮细胞相互作用。肿瘤微环境（TME）中的细胞、免疫细胞、信号分子和细胞外基质。宿主和癌细胞之间的相互作用很复杂，其作用可能是肿瘤抑制或例如，巨噬细胞首先被招募来对抗癌症；然而，巨噬细胞与癌症相互作用。细胞可以使它们支持肿瘤，从而使人们能够更好地了解肿瘤的复杂性。癌细胞与其微环境之间的相互作用可以更好地理解机制耐药性、识别新的分子靶点并帮助解决治疗中大量未满足的需求癌症的定量技术，例如我们的技术，整合了离体药物治疗和评估。天然组织中细胞和分子表型的药理反应应该会加速新疗法的发现和开发。然而，目前研究药物反应和 TME 的工具尚未满足药物测试的需求。几乎无限数量的潜在组合和有限的资源来实际测试它们，非常需要用于使用人类完整肿瘤组织离体预测体内组合反应的测试平台小型化、多重形式的免疫疗法，保留尽可能多的 TME。在我们的第一个 R01 周期中，我们开发了一个微流体平台（称为 Oncoslice），可以选择性地将器官型培养物时空暴露于数十种药物条件下，我们证明了其实用性在第二个 R01 周期中，我们的目标是应用我们的异种移植物和患者 GBM 切片的细胞死亡测定。 Oncoslice 平台用于评估联合免疫疗法及其与 TME 的相互作用。平台将应用于两种难以治疗的实体瘤类型——胰腺癌（PCa、小鼠和人类）我们最近发现 CD8+ T 细胞在肿瘤内迁移。是胰腺免疫检查点抑制剂治疗产生抗肿瘤活性的必要前体癌症证实了我们的断言，即发展对细胞与细胞相互作用的微观理解 TME 至关重要。PCa 和 TNBC 都具有极大的异质性，并且对当前的免疫反应不佳。我们平台的新开发将包括动态变化的实时成像。我们将进行免疫 TME、组织和细胞因子采样、选择性转录组学和蛋白质通路分析。将切片中的表型反应与分子数据整合起来，共同构建预测统计模型。这些方法将为免疫调节药物发现建立一个创新平台，旨在深入了解药物的作用机制以及 TME 在癌症治疗中的作用。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Organotypic Models for Functional Drug Testing of Human Cancers.

人类癌症功能药物测试的器官模型。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Huang, Yu Ling;Dickerson, Lindsay K;Kenerson, Heidi;Jiang, Xiuyun;Pillarisetty, Venu;Tian, Qiang;Hood, Leroy;Gujral, Taranjit S;Yeung, Raymond S
通讯作者：
Yeung, Raymond S

3D-Printed Microfluidics.

3D 打印微流体。

DOI：
10.1002/anie.201504382
发表时间：
2016-03-14
期刊：
Angewandte Chemie
影响因子：
0
作者：
Au AK;Huynh W;Horowitz LF;Folch A
通讯作者：
Folch A

Digital Manufacturing of Selective Porous Barriers in Microchannels Using Multi-Material Stereolithography.

使用多材料立体光刻技术数字化制造微通道中的选择性多孔屏障。

DOI：
发表时间：
2018-03-14
期刊：
影响因子：
3.4
作者：
Kim, Yong Tae;Castro, Kurt;Bhattacharjee, Nirveek;Folch, Albert
通讯作者：
Folch, Albert

High-Precision Stereolithography of Biomicrofluidic Devices.

生物微流体装置的高精度立体光刻。

DOI：
发表时间：
2019-06
期刊：
影响因子：
6.8
作者：
Kuo, Alexandra P;Bhattacharjee, Nirveek;Lee, Yuan;Castro, Kurt;Kim, Yong Tae;Folch, Albert
通讯作者：
Folch, Albert

Microdissected "cuboids" for microfluidic drug testing of intact tissues.

用于完整组织微流体药物测试的显微解剖“长方体”。

DOI：
发表时间：
2021-01-05
期刊：
影响因子：
6.1
作者：
Horowitz, Lisa F;Rodriguez, Adan D;Au;Bishop, Kevin W;Barner, Lindsey A;Mishra, Gargi;Raman, Aashik;Delgado, Priscilla;Liu, Jonathan T C;Gujral, Taranjit S;Mehrabi, Mehdi;Yang, Mengsu;Pierce, Robert H;Folch, Albert
通讯作者：
Folch, Albert