Biological Imaging Core

生物成像核心

• 批准号: 7782254
• 负责人: JOHANNES CZERNIN
• 金额: $ 35.53万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782254
• 关键词: Acyclovir; Adoptive Cell Transfers; Adoptive Transfer; Affinity; Animal Cancer Model; Animal Model; Arts; Biological; Bioluminescence; Cell Count; Cell Cycle Kinetics; Cell Therapy; Cells; Clinical; Clinical Immunology; Clinical Protocols; Clinical Trials; Collaborations; Complement; Consensus; Data; Data Analyses; Deposition; Development; Diagnostic; Engineering; Generations; Genetic; Goals; Guanine; Hematopoietic stem cells; Herpesvirus 1; Human; Image; Imaging Techniques; Immune response; Immunologic Monitoring; Immunotherapy; In Vitro; Institution; Kinetics; Life; Lymphocyte; Lymphoid; Malignant Neoplasms; Mature T-Lymphocyte; Measurement; Metastatic Melanoma; Methods; Modeling; Modification; Monitor; Optics; Organ; Organism; Patients; Population; Positron-Emission Tomography; Program Research Project Grants; Protocols documentation; Reporter Genes; Reporting; Reproducibility; Research; Research Infrastructure; Research Personnel; Resolution; Sampling Errors; Scanning; Signal Transduction; Site; Stem cell transplant; Structure; System; T-Lymphocyte; Techniques; Technology; Therapeutic; Thymidine Kinase; Transplantation; Treatment Efficacy; Variant; Work; X-Ray Computed Tomography; abstracting; analog; base; cancer cell; cancer immunotherapy; cellular engineering; data acquisition; gene therapy; genetically modified cells; imaging modality; improved; in vivo; melanoma; molecular imaging; novel; optical imaging; peripheral blood; pre-clinical; programs; research study; response; scientific organization; software systems; suicide gene; tool; trafficking; tumor; whole body imaging

ABSTRACT: Novel adoptive T cell therapies have enabled long lasting objective clinical responses in a significant proportion of patients with metastatic melanoma. Treatment efficacy and availability could be further improved by ex vivo genetic modification of lymphocytes allowing generation of large numbers of cells with enhanced anti-tumor function. The development of such adoptive cell transfer immune therapies is critically dependent on the availability of tools to track the distribution of genetically modified lymphocytes following transplantation in melanoma patients. Work by Program Project Grant (PPG) Investigators in animal models of cancer and in humans has demonstrated that this goal could be accomplished using novel molecular imaging techniques such as Positron Emission Tomography (PET). To visualize the distribution of genetically modified T lymphocytes and Hematopoietic Stem Cells transplanted in melanoma patients, these cells will be engineered to express a PET reporter gene derived from the Herpes Simplex Virus 1 thymidine kinase (HSVI-tk). HSVI-tk has been used extensively in clinical trials as a "suicide gene" and has a very high affinity for the PET probe (9-[4-[(18)F]fluoro-3-(hydroxymethyl)-butyl]guanine) (9(18)'F]FHBG). [9(18)F]FHBG administered in trace amounts accumulates specifically in cells expressing HSVI-tk and resulting signals can be detected by PET. We will use this technique for in vivo "counting" of genetically modified cells at various sites throughout the body, including lymphoid organs and metastatic melanoma deposits. Such measurements cannot be performed using conventional technologies and could provide eariy prediction markers for therapeutic responses. To support imaging studies by PPG Investigators, we propose to establish a Biological Imaging Core for noninvasive monitoring of immune responses. This Core will complement state-of-the-art 'in vitro' immUne monitoring measurements described in Core A and will enable PPG Investigators to pertorm preclinical and clinical 'in vivo' immune monitoring studies using multiple imaging modalities. The proposed Core will take advantage of the unique expertise and infrastructure for functional and anatomical tomographic imaging already available at UCLA and will also coordinate preclinical imaging experiments performed at other participating institutions. We envision that the Imaging Core will help cement long-term interactive multi-institutional collaborations involving experts in imaging, gene therapy, basic and clinical immunology, who are at the forefront of cancer immunotherapy transitional research.

摘要：新型过继性 T 细胞疗法已在相当大比例的转移性黑色素瘤患者中实现了长期持续的客观临床反应。通过对淋巴细胞进行离体基因修饰，可以产生大量具有增强抗肿瘤功能的细胞，从而进一步提高治疗效果和可用性。这种过继性细胞转移免疫疗法的发展很大程度上取决于追踪黑色素瘤患者移植后转基因淋巴细胞分布的工具的可用性。计划项目拨款 (PPG) 研究人员在癌症动物模型和人类中的工作表明，使用正电子发射断层扫描 (PET) 等新颖的分子成像技术可以实现这一目标。 为了可视化移植到黑色素瘤患者体内的转基因 T 淋巴细胞和造血干细胞的分布，这些细胞将被设计为表达源自单纯疱疹病毒 1 胸苷激酶 (HSVI-tk) 的 PET 报告基因。 HSVI-tk已作为“自杀基因”广泛应用于临床试验，并且与PET探针（9-[4-[(18)F]氟-3-(羟甲基)-丁基]鸟嘌呤）具有非常高的亲和力(9(18)'F]FHBG)。微量施用的 [9(18)F]FHBG 会在表达 HSVI-tk 的细胞中特异性积累，并且可以通过 PET 检测到产生的信号。我们将使用这种技术对基因进行体内“计数” 全身不同部位的细胞被修饰，包括淋巴器官和转移性黑色素瘤 存款。这种测量无法使用传统技术进行，但可以提供早期 治疗反应的预测标记。 为了支持 PPG 研究人员的成像研究，我们建议建立一个用于非侵入性的生物成像核心 监测免疫反应。该核心将补充最先进的“体外”免疫 监测核心 A 中描述的测量结果将使 PPG 研究人员能够执行临床前和 使用多种成像方式进行临床“体内”免疫监测研究。 拟议的核心将利用功能和解剖学方面独特的专业知识和基础设施 加州大学洛杉矶分校已提供断层扫描成像，并将协调临床前成像实验 在其他参与机构进行。我们预计成像核心将有助于巩固长期 交互式多机构合作，涉及影像、基因治疗、基础和临床专家 免疫学，他们处于癌症免疫治疗过渡研究的前沿。