Optimizing systemic immunotherapy for personalized brain metastasis treatment

优化全身免疫疗法以实现个性化脑转移治疗

基本信息

批准号：
10706497
负责人：
Michael Lim
金额：
$ 34.73万
依托单位：
STANFORD UNIVERSITY
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：
2021-09-21 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706497
关键词：
3-Dimensional Ablation Adoptive Transfer Air Antigen Presentation Antigen-Presenting Cells Antigens Antitumor Response Autologous Biological Assay Brain Brain Drains Brain Neoplasms Breast Breast Cancer Cell CD8-Positive T-Lymphocytes Cancer cell line Cell Communication Cells Cephalic Cytotoxic T-Lymphocytes Data Distal Drops Exhibits Flow Cytometry Future ITGAM gene Immune Immune checkpoint inhibitor Immune response Immunity Immunomodulators Immunosuppression Immunotherapy Infiltration Injections Interferon Type II Interruption Intracranial Neoplasms Kidney Knock-out Knockout Mice Lesion Liquid substance Lung Lymphocyte Malignant Neoplasms Measurement Measures Mediating Metastatic malignant neoplasm to brain Modeling Monitor Mus Myelogenous Myeloid Cells Neoplasm Metastasis Neuroimmune Organoids Pathologic Pathway interactions Patients Peripheral Blood Mononuclear Cell Pluripotent Stem Cells Positron-Emission Tomography Production Prognosis Proliferating Role Signal Transduction Site Skin Specimen Splenocyte T cell clonality T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Therapeutic Transforming Growth Factor beta Transgenic Mice Tropism Tumor-associated macrophages Vaccinated Vaccination Vaccines anti-PD-1 anti-PD1 therapy anti-tumor immune response cancer cell cancer infiltrating T cells cytotoxic design draining lymph node immune checkpoint immune checkpoint blockade immunoregulation induced pluripotent stem cell inhibitor insight lung cancer cell lymph nodes melanoma migration mouse model novel personalized immunotherapy reconstitution recruit spatiotemporal subcutaneous synergism treatment strategy tumor tumor progression vaccination strategy

项目摘要

ABSTRACT – PROJECT 3 By definition, when patients develop brain metastasis (BM) from their systemic cancer, they become stage IV and their prognosis drops to under a year. While the mechanism behind brain-tropism of different tumors (Project 1) and the role of resident immune cells in supporting brain metastasis (Project 2) need to be elucidated, there is also a gap in our understanding of how brain tumors represent an inflection point in patient survival and anti- tumor response. We have previously observed evidence of intracranial metastases dampening the immune response mounted by cytotoxic T lymphocytes. Understanding the mechanism by which tumor-associated macrophages (TAMs) recruited to BMs exert said immunosuppression is crucial for the successful treatment of brain metastasis. We propose to study the role of TAMs in dampening T cell priming via a TGF-β mediated pathway. We hypothesize that TGF-β released by TAMs in the BM act at the level of the draining lymph nodes to induce global immunosuppression. We believe that blockade of TGF-β at the lymph nodes will augment an antitumor immune response induced by checkpoint-blockade or vaccination strategies (such as with induced pluripotent stem cells or iPSCs). To test our hypothesis, we will investigate the: i) migration of TAMs to BMs and tumor draining lymph nodes and its effects on T cell priming, ii) role of TGF-β secreted by the TAMs in mediating said immunosuppression at the level of the draining lymph nodes, and iii) synergy of inhibiting TGF-β signaling and iPSC vaccines to treat BMs. We expect that the data generated from these studies will provide novel insights into a previously unexplored mechanism by which BM-infiltrating TAMs exert systemic immunosuppression and open new avenues for the design of future therapeutic strategies to treat patients with brain metastasis.

摘要 - 项目3 根据定义，当患者从全身性癌症中发展出脑转移（BM）时，他们成为IV期他们的预后下降到不到一年。而不同肿瘤的脑部吸引力背后的机制（项目 1）居民在支撑大脑转移中的作用（项目2）需要阐明，那里我们对脑肿瘤如何代表患者存活和抗脑的感染点的理解也是一个差距肿瘤反应。我们以前已经观察到颅内转移酶导致免疫的证据通过细胞毒性T淋巴细胞安装的反应。了解与肿瘤相关的机制招募到BMS的巨噬细胞（TAM）表示，免疫抑制对于成功治疗至关重要脑转移。我们建议研究TAM在通过TGF-β介导的破坏T细胞启动中的作用路径。我们假设TAM在BM ACT中释放的TGF-β在排水淋巴结的水平上诱导全球免疫抑制。我们认为，在淋巴结处的TGF-β封锁将增加由检查点阻滞或疫苗接种策略引起的抗肿瘤免疫响应（例如多能干细胞或IPSC）。为了检验我们的假设，我们将研究：i）TAM迁移到BMS和肿瘤排出淋巴结及其对T细胞启动的影响，ii）TAM在介导中分泌的TGF-β的作用在排水淋巴结的水平上说免疫抑制，iii）抑制TGF-β信号的协同作用和IPSC疫苗以治疗BMS。我们预计从这些研究产生的数据将提供新颖的见解成为以前出乎意料的机制，通过该机制，BM浸润TAM会发挥全身免疫抑制和开放新的途径，以设计未来治疗脑转移患者的治疗策略。