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Development of Physiologic Tissue Models to Assess Tumor Explant Response to Immune Checkpoint Blockade

开发生理组织模型来评估肿瘤外植体对免疫检查点封锁的反应

基本信息

批准号：
10250392
负责人：
David A Barbie
金额：
$ 82.64万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250392
关键词：
3-Dimensional Animal Model Antigens Back Basic Science Biological Assay Biological Models Blood Vessels CTLA4 gene Cancer Patient Cell Communication Cell Culture Techniques Cell Proliferation Cell Survival Cell physiology Cells Cellular Structures Chronic Clinical Clinical Trials Combined Modality Therapy Complex Conditioned Culture Media Data Dendritic Cells Development Effector Cell Endothelial Cells Engineering Enrollment Evaluation Evolution Extracellular Matrix Extravasation Fibroblasts Flow Cytometry Gel Goals Growth Growth Factor Human Immune Immune Targeting Immune checkpoint inhibitor Immune response Immunofluorescence Immunologic Immunotherapy In Vitro Investigation Knowledge Malignant Neoplasms Malignant neoplasm of thyroid Measurement Measures Microfluidic Microchips Microfluidics Modeling Monitor Mus Myeloid Cells Organoids PD-1 inhibitors PD-1/PD-L1 Patients Phenotype Physiological Population Primary Neoplasm Protocols documentation Public Health Research Research Project Grants Resistance Running Sampling Side Signal Transduction Specimen Support System System T-Lymphocyte TBK1 gene Techniques Technology Time Tissue Model Translational Research Tumor Biology Tumor Tissue Tumor-Derived Tumor-infiltrating immune cells Validation Vascular System Work anti-CTLA4 anti-CTLA4 antibodies anti-PD-1 anti-PD-1/PD-L1 anti-PD1 antibodies anticancer research base cancer cell cancer immunotherapy cancer type cell growth cell killing cell motility checkpoint therapy chemokine clinical decision-making cytokine diagnostic platform experience experimental study immune activation immune checkpoint immune checkpoint blockade immune function in vivo individual patient inhibitor/antagonist macrophage melanoma monocyte neoplastic cell novel patient response patient subsets physiologic model predicting response predictive marker predictive tools response standard of care targeted treatment trafficking tumor tumor microenvironment

项目摘要

PROJECT SUMMARY The goal of this research project proposal is to develop a physiologic model of ex vivo tumor culture to study responsiveness to immune checkpoint blockade. Although inhibitors of the PD-1/PD-L1 and CTLA4 immune checkpoints have led to remarkable and durable responses in cancers such as malignant melanoma, the ability to predict the activity for individual patients remains limited, and have relied on measurements from fixed tumor tissue. While the ability to grow patient derived tumors in organoid models, for example, has been rigorously demonstrated over the past several years, these systems lack key features of the tumor microenvironment, including a vascular network and immune cells. Thus, an ex vivo system that supports tumor and immune cell culture by recapitulating a physiologic microenvironment will almost certainly be essential to the development of functional assays that can predict patient response to immunotherapy. Recently, we demonstrated that our three-dimensional microfluidic culture system can support growth of primary human tumor spheroids derived from multiple different cancer types, including melanoma. Importantly, immune profiling of the cells within the spheroids reveals that they also contain a significant proportion of tumor associated immune cells, including macrophages, dendritic cells, and antigen experienced T lymphocytes. Exposure of these short term spheroid cultures to immune checkpoint inhibitors such as anti- PD1 antibodies results in evidence of immunologic response and robust cytokine secretion into conditioned medium, as well as evidence of cell killing in some cases. The broad, long term objective of this proposal is to extend this preliminary model to leverage the capabilities developed in our labs to incorporate a microcirculatory network in the 3D matrix surrounding the tumor and use this as a means of subsequently introducing selected myeloid cells. Both the initial model and these extensions to it will be subject to detailed validation in order to develop a realistic physiologic culture system that enables prediction of immunotherapy response. A unique aspect of this work is that it spans basic and translational research, including the use of animal models to help engineer vascularized networks, and patient-derived samples and clinical response to immune checkpoint blockade to validate the system. Specific aims are to: 1) Refine and validate an existing microfluidic tumor culture model to assess response to immune checkpoint inhibitor therapies 2) Incorporate vascular flow of immune cells to monitor extravasation and expansion of immune effector cells in tumor culture, and 3) Directly compare ex vivo experiments with patient specific response to immune checkpoint blockade. Through these complementary studies, the ultimate goal is to develop a robust model that can eventually be adapted to clinical use to help target immune checkpoint inhibitor therapies to the appropriate subgroup of patients. This basic platform will also be useful in other settings, once it has been fully evaluations

项目总结本研究项目提案的目标是开发一种体外肿瘤培养的生理模型，以研究对免疫检查点封锁的反应性。尽管PD-1/PD-L1和CTLA4的抑制剂免疫检查点对恶性黑色素瘤等癌症患者产生了显著而持久的反应，预测单个患者活动的能力仍然有限，并依赖于从固定肿瘤组织。例如，在器官模型中生长患者来源的肿瘤的能力一直是经过过去几年的严格证明，这些系统缺乏肿瘤的关键特征。微环境，包括血管网络和免疫细胞。因此，体外系统支持通过概括肿瘤和免疫细胞培养的生理微环境，几乎可以肯定对于开发能够预测患者对免疫治疗的反应的功能分析是必不可少的。最近，我们展示了我们的三维微流控培养系统可以支持生长。来自多种不同癌症类型的原发人类肿瘤球体，包括黑色素瘤。重要的是，免疫图谱显示球体内的细胞也含有显著的肿瘤相关免疫细胞的比例，包括巨噬细胞、树突状细胞和抗原 T淋巴细胞。将这些短期球体培养物暴露于免疫检查点抑制剂，如抗- PD1抗体导致免疫应答和强大的细胞因子分泌到条件在某些情况下，还有细胞死亡的证据。这项提案的广泛、长期目标是扩展这一初步模式，以利用我们的实验室开发的功能将微循环网络整合到围绕肿瘤，并利用它作为一种手段，随后引入选定的髓系细胞。初始模型和这些扩展将经过详细的验证，以发展一种现实的生理文化能够预测免疫治疗反应的系统。这项工作的一个独特之处是它跨越了基本的和翻译研究，包括使用动物模型来帮助设计血管网络，以及患者获取的样本和临床对免疫检查点封锁的反应来验证该系统。特定的目的是：1)改进和验证现有的微流控肿瘤培养模型以评估对免疫的反应检查点抑制疗法2)结合免疫细胞的血管流动来监测外渗和肿瘤培养中免疫效应细胞的扩增，以及3)体外实验与患者的直接比较对免疫检查点封锁的特定反应。通过这些互补性研究，最终目标是开发一种最终可用于临床的健壮模型，以帮助针对免疫检查点针对适当的患者亚组进行抑制剂治疗。这个基础平台也将在其他方面有用设置，一旦进行了充分评估

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）

The effects of luminal and trans-endothelial fluid flows on the extravasation and tissue invasion of tumor cells in a 3D in vitro microvascular platform.

DOI：
10.1016/j.biomaterials.2020.120470
发表时间：
2021-01
期刊：
Biomaterials
影响因子：
14
作者：
Hajal C;Ibrahim L;Serrano JC;Offeddu GS;Kamm RD
通讯作者：
Kamm RD

Vascularized organoids on a chip: strategies for engineering organoids with functional vasculature.

DOI：
10.1039/d0lc01186j
发表时间：
2021-02-09
期刊：
Lab on a chip
影响因子：
6.1
作者：
Zhang S;Wan Z;Kamm RD
通讯作者：
Kamm RD

Interstitial flow promotes macrophage polarization toward an M2 phenotype.

DOI：
10.1091/mbc.e18-03-0164
发表时间：
2018-08-08
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Li R;Serrano JC;Xing H;Lee TA;Azizgolshani H;Zaman M;Kamm RD
通讯作者：
Kamm RD

Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment.

集成巨噬细胞响应肿瘤微环境中的物理和化学因素的计算机模拟和 3D 体外模型。

DOI：
10.1093/intbio/zyaa007
发表时间：
2020
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
0
作者：
Lee,SharonWeiLing;Seager,RJ;Litvak,Felix;Spill,Fabian;Sieow,JeLin;Leong,PennyHweixian;Kumar,Dillip;Tan,AlrinaShinMin;Wong,SiewCheng;Adriani,Giulia;Zaman,MuhammadHamid;Kamm,AndRogerD
通讯作者：
Kamm,AndRogerD

The effects of monocytes on tumor cell extravasation in a 3D vascularized microfluidic model.