Non-invasive imaging of the anti-tumor immune response

抗肿瘤免疫反应的非侵入性成像

基本信息

批准号：
10318578
负责人：
Hidde L. Ploegh
金额：
$ 57.59万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-14 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10318578
关键词：
Address Affinity Animals Antibodies Antigens Blocking Antibodies CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology CTLA4 gene CXCL10 gene CXCL9 gene CXCR3 gene Cancer Model Cells Cellular biology Chemicals Chemistry Chemotactic Factors Chimeric Proteins Colorectal Neoplasms Coupled Cytotoxic T-Lymphocytes Data Development Diagnosis Diagnostic Effectiveness Engineering Ensure Equilibrium Etiology Failure Fibronectins Gene Expression Genes Genetic Half-Life Human Papillomavirus Human papillomavirus 16 ITGAM gene Image Imaging Device Immune ImmunoPET Immunoglobulin Fragments Immunotherapy Infiltration Isotopes Knock-out Ligands Light MC38 MHC Class I Genes Malignant Neoplasms Methods Modeling Modification Molecular Analysis Monitor Mus Myelogenous Myeloid Cells Non-Invasive Cancer Detection Outcome PTPRC gene Penetration Play Positron-Emission Tomography Predisposition Proteins RNA Splicing Role Specificity Surface T cell therapy T-Lymphocyte Technology Th1 Cells Therapeutic Effect Tissues Tumor Antigens Tumor-infiltrating immune cells Validation Variant anti-CTLA4 antibodies anti-PD-1 anti-PD1 therapy anti-tumor immune response antigen detection antigen-specific T cells base cancer imaging cancer therapy chemokine chemokine receptor comparative cytokine design differential expression effective therapy effector T cell experimental study image reconstruction imaging agent imaging approach immune checkpoint blockade immunoengineering immunological intervention immunological status improved innovation insight interest macrophage melanoma nanobodies neovasculature new technology non-invasive imaging novel patient subsets pre-clinical prognostic tool programmed cell death ligand 1 prospective receptor recruit responders and non-responders response single cell analysis single-cell RNA sequencing success theranostics therapy outcome tool transcriptome treatment response tumor tumor microenvironment

项目摘要

Project Summary Immunotherapy using checkpoint blockade has revolutionized cancer treatment. The outcome of therapy directly results from changes imposed on the tumor microenvironment (TME) by checkpoint blockade. However, only a subset of patients respond. What controls this disparity is poorly understood. We propose to develop and apply tools that can help differentiate responders from non-responders in different pre-clinical tumor models soon after the start of treatment. We have shown that immuno-positron emission tomography (Immuno-PET) can be used to monitor infiltration status of specific subsets of immune cells, namely T cells and myeloid cells. We use small (~15 kDa) camelid-derived single domain antibodies (nanobodies) that have nM to pM affinity for their targets to perform immuno-PET imaging. Our unique chemical approaches provide imaging agents of unprecedented quality and sensitivity. Even cells that display proteins of relatively low abundance such as CTLA-4 can be clealrly imaged. We have shown in several (syngeneic) tumor models that monitoring the dynamics of cytotoxic T cells in the TME can be used to distinguish early responders from non-responders. This observation has allowed us to stratify animals into responders and non-responders, then excise their tumors, isolate the immune infiltrating cells, and subject these to single-cell RNA sequencing. These data show that the myeloid compartment and the cytokines and chemokines it produces, plays a major role in determining the outcome of anti PD-1 treatment. We propose to expand these initial findings to additional mouse tumor models, given the distinct cells of origin that give rise to them and their differences in susceptibility to immune intervention. This project is aimed at bringing to light key changes that take place in the TME early on, using immuno-PET. Our complementary molecular analyses will help design more effective therapies. Macrophages and DCs in the TME of responders produce CXCL9, a chemoattractant for cytotoxic T cells that helps maintain their activated state. This chemokine is therefore a key player in the outcome of anti-PD-1 therapy. We thus propose to re-engineer the TME by using chemistry to make novel CXCL9-fusion proteins and deliver them to the TME. Single-domain antibodies are perfect candidates for such fusions. Their small size allows excellent tissue penetration and their high affinity ensures efficient delivery to, and retention in, the TME. Imaging the distribution of CXCL9 or its receptor will shed further light on the anti-tumor immune status. We will therefore generate nanobodies as imaging agents specific for such cytokines and their receptors.

项目摘要使用检查点封锁的免疫疗法彻底改变了癌症治疗。直接治疗的结果由检查点阻塞对肿瘤微环境（TME）施加的变化的结果。但是，只有一个患者子集反应。控制这种差异的原因知之甚少。我们建议开发和应用可以在不同的临床前肿瘤模型中有助于区分响应者和非反应者的工具治疗的开始。我们已经表明，可以使用免疫峰值发射断层扫描（Immuno-PET）监测免疫细胞（即T细胞和髓样细胞）特定亚群的浸润状态。我们使用小（〜15 kDa）骆驼衍生的单域抗体（纳米抗体）具有NM至PM亲和力的目标执行免疫-PET成像。我们独特的化学方法提供了前所未有的成像剂质量和灵敏度。甚至显示出相对较低丰度（例如CTLA-4）的蛋白质的细胞也可以被抓住成像。我们已经在几种（合成）肿瘤模型中显示了监测细胞毒性T细胞动力学在TME中，可用于区分早期响应者和非反应者。这个观察使我们将动物分层为反应者和无反应者，然后进行切除肿瘤，分离出免疫浸润细胞，并对它们进行单细胞RNA测序。这些数据表明髓样舱和它产生的细胞因子和趋化因子在确定抗PD-1治疗的结果中起着重要作用。我们建议将这些初始发现扩展到其他小鼠肿瘤模型，鉴于原点的不同细胞这引起了它们及其在免疫干预的易感性方面的差异。这个项目针对使用Immuno-PET，在TME早期发生的钥匙键变化。我们的补充分子分析将有助于设计更有效的疗法。响应者TME中的巨噬细胞和DC 产生CXCL9，这是一种用于维持其活化状态的细胞毒性T细胞的趋化剂。这个趋化因子因此，是抗PD-1治疗结果的关键人物。因此，我们建议通过使用化学以使新型CXCL9融合蛋白并将其输送到TME。单域抗体是完美的融合候选人。它们的小尺寸可允许出色的组织穿透和高亲和力确保有效地交付并保留在TME中。成像CXCL9或其受体的分布将脱落进一步阐明抗肿瘤免疫状态。因此，我们将产生纳米体作为特定成像剂对于这种细胞因子及其受体。