(PQC4) Imaging CD8 T Cells In Tumor Immunotherapy By Immunopet

(PQC4) 在肿瘤免疫治疗中对 CD8 T 细胞进行成像 Immunopet

基本信息

批准号：
8928583
负责人：
Anna M Wu
金额：
$ 20.1万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2014-09-17 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928583
关键词：
Address Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigens B-Lymphocytes Binding Biological Biological Assay Blood Bypass CD4 Positive T Lymphocytes CD8B1 gene CT26 Cancer Biology Cell Count Cell Therapy Cell physiology Cell surface Cells Cessation of life Complex Cysteine Cytokine Activation Cytotoxic T-Lymphocyte-Associated Protein 4 Cytotoxic T-Lymphocytes Data Detection Development Engineering Evaluation Exhibits Flow Cytometry Half-Life Health Helper-Inducer T-Lymphocyte Human Image Immune Immune Cell Activation Immune response Immunoglobulin Fragments Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Infiltration Kinetics Label Life Location Lymphoid Tissue MS4A1 gene Malignant Neoplasms Metabolic Metabolism Modeling Monitor Mus Organism Participant Pharmaceutical Preparations Phenotype Play Positron Positron-Emission Tomography Pre-Clinical Model Radioimmunoconjugate Radiolabeled Rattus Role Site Spleen T-Cell Activation T-Cell Depletion T-Cell Proliferation T-Lymphocyte Therapeutic Therapeutic antibodies Therapy Evaluation Time Tissues Tracer Tumor Biology Vaccines Wild Type Mouse Work antibody engineering base cancer cell cancer immunotherapy cancer therapy cell type contrast imaging cytokine cytotoxic dimer fluorodeoxyglucose imaging agent imaging modality immune activation immunoreactivity improved in vivo lymph nodes molecular imaging mouse model neoplasm immunotherapy neovasculature non-invasive imaging novel programs quantitative imaging radiotracer receptor response success tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Tumors are comprised of a variety of cell types in addition to the malignant cells, including stroma, vasculature, and infiltrating immune cells. An understanding of the identities, numbers, and states of these other cellular components is clearly important to understanding the biology of tumors, and their responses to therapy, as outlined in the NCI Provocative Question C4. Recently, immune-modulatory therapies and adoptive cell therapies have become established as powerful therapeutic approaches in cancer, raising a critical need to be able to monitor immune responses directly within tumors. Positron emission tomography (PET) provides highly sensitive, non-invasive and quantitative imaging, which can be combined with antibody-based probes to provide molecular imaging of tissues and cells in vivo based on cell surface phenotype. Furthermore, engineered antibody fragments (such as cys-diabodies; covalent dimers of single-chain antibody fragments) have been generated with optimal kinetics enabling rapid in vivo targeting and clearance for imaging applications by immunoPET. In the proposed work, immunoPET using engineered antibody fragments that recognize CD8, a classic cell surface marker on cytotoxic T cells, will be developed to address the challenge of direct imaging of immune cell subsets in tumors. Specific Aim 1 will focus on the need for imaging agents to be biologically inert, and will assess biological effects (activation, cytokine release) of treating T cells with anti- CD8 cys-diabodies,in vitro and in vivo. Specific Aim 2 will employ radiolabeled anti-CD8 cys-diabodies for immunoPET assessment of immune activation in normal mice and tumor-bearing mice treated with immune stimulants such as anti-CD137 antibodies. Specific Aim 3 will focus on immunoPET detection and quantification of CD8+T cells in tumor-bearing mice treated with antibodies that reverse immunosuppression (such as anti-PD-1 and anti-CTLA-4) and induce tumor infiltration by cytotoxic T cells. These studies will validate the role of immunoPET probes for CD8+ T cells to study responses to cancer immunotherapy in vivo, provide a deeper understanding of immune responses in living organisms, and will open the door to broad methods for imaging and quantitating immune cell subsets in preclinical models and eventually humans.

描述（由申请人提供）：除恶性细胞（包括基质，脉管系统和浸润的免疫细胞）外，肿瘤还包括多种细胞类型。如NCI挑衅性问题C4所述，对这些其他细胞成分的身份，数量和状态的理解显然很重要，它们对治疗的反应很重要。最近，免疫调节疗法和收养细胞疗法已成为癌症中强大的治疗方法，从而提出了能够直接监测肿瘤中的免疫反应的迫切需要。正电子发射断层扫描（PET）提供了高度敏感，非侵入性和定量成像，可以与基于抗体的探针结合使用，以基于细胞表面表型在体内提供组织和细胞的分子成像。此外，已经用最佳动力学生成了工程化抗体片段（例如Cys-二氧化碳；单链抗体片段的共价二聚体），从而使体内靶向快速靶向和通过Immunopet进行成像的清除率。在拟议的工作中，将开发出使用工程抗体片段的免疫集，这些抗体片段识别CD8是细胞毒性T细胞上经典细胞表面标记，以应对肿瘤中免疫细胞亚群直接成像的挑战。具体目标1将集中于成像剂在生物学上惰性的需求，并将评估用抗CD8 CYS-二氧化阳的处理T细胞的生物学作用（激活，细胞因子释放），体外和体内。具体的目标2将采用放射标记的抗CD8 Cys-糖 - 在正常小鼠和用免疫刺激剂（例如抗CD137抗体）治疗的正常小鼠和承重肿瘤的小鼠中进行免疫激活评估。具体的目标3将重点放在用抗体抑制免疫抑制（例如抗PD-1和抗CTLA-4）的抗体处理的肿瘤小鼠中的CD8+T细胞的免疫物检测和定量，并通过细胞毒性T细胞诱导肿瘤浸润。这些研究将验证CD8+ T细胞的免疫集探针在研究体内对癌症免疫疗法的反应，对生物体中的免疫反应的更深入了解，并将为在陶醉杆菌模型和最终人类中进行成像和定量免疫细胞亚群的广泛方法打开大门。