(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

• 批准号: 8791842
• 负责人: Anna M Wu
• 金额: $ 16.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/8791842
• 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; 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; 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; cytokine; cytotoxic; dimer; fluorodeoxyglucose; imaging modality; immune activation; immunoreactivity; improved; in vivo; lymph nodes; molecular imaging; mouse model; neovasculature; novel; programs; public health relevance; radiotracer; receptor; response; success; tumor; tumor growth

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）：除恶性细胞外，肿瘤还包含多种细胞类型，包括基质、脉管系统和浸润性免疫细胞。正如 NCI 挑衅性问题 C4 中所述，了解这些其他细胞成分的身份、数量和状态对于了解肿瘤的生物学及其对治疗的反应显然很重要。最近，免疫调节疗法和过继细胞疗法已成为癌症的强大治疗方法，因此迫切需要能够直接监测肿瘤内的免疫反应。正电子发射断层扫描（PET）提供高灵敏度、非侵入性和定量成像，可以与基于抗体的探针结合，根据细胞表面表型提供体内组织和细胞的分子成像。此外，工程化抗体片段（例如 cys-双价抗体；单链抗体片段的共价二聚体）已以最佳动力学生成，能够快速体内靶向和清除，用于免疫 PET 成像应用。在拟议的工作中，将开发使用识别 CD8（细胞毒性 T 细胞的经典细胞表面标记物）的工程化抗体片段的免疫 PET，以解决肿瘤中免疫细胞亚群直接成像的挑战。具体目标 1 将重点关注成像剂具有生物惰性的需求，并将评估用抗 CD8 cys-双抗体处理 T 细胞的体外和体内生物效应（激活、细胞因子释放）。具体目标 2 将采用放射性标记的抗 CD8 cys-双抗体对正常小鼠和接受抗 CD137 抗体等免疫刺激剂治疗的荷瘤小鼠的免疫激活进行免疫PET评估。具体目标 3 将重点关注经抗体治疗的荷瘤小鼠中 CD8+T 细胞的免疫 PET 检测和定量（例如抗 PD-1 和抗 CTLA-4）并诱导细胞毒性 T 细胞浸润肿瘤。这些研究将验证 CD8+ T 细胞的免疫 PET 探针在研究体内癌症免疫治疗反应中的作用，提供对生物体免疫反应的更深入了解，并将为临床前免疫细胞亚群成像和定量的广泛方法打开大门。模型，最终是人类。