Biological Imaging Core

摘要：在相当大比例的转移性黑色素瘤患者中，新的过继T细胞疗法使长期的客观临床反应成为可能。通过对淋巴细胞进行体外遗传修饰，可以进一步提高治疗效果和有效性，从而产生大量具有增强抗肿瘤功能的细胞。这种过继细胞转移免疫疗法的发展严重依赖于工具的可用性，以跟踪黑色素瘤患者移植后转基因淋巴细胞的分布。项目资助计划(PPG)的研究人员在癌症动物模型和人类中的工作表明，可以使用正电子发射断层扫描(PET)等新的分子成像技术来实现这一目标。 为了观察移植在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，将对这些细胞进行工程改造，以表达源于单纯疱疹病毒1型胸苷激酶(HSVI-tk)的PET报告基因。HSVI-tk作为一种自杀基因已被广泛应用于临床试验，并与(9-[4-[(18)F]fluoro-3-(hydroxymethyl)-butyl]guanine)(9(18)‘F]FHBG具有很高的亲和力。[9(18)F]FHBG微量地在表达HSVI-tk的细胞中聚集，由此产生的信号可以被PET检测到。我们将使用这项技术在体内进行基因计数 体内不同部位的修饰细胞，包括淋巴器官和转移性黑色素瘤 押金。这样的测量不能使用传统技术进行，并且可以提供早期 治疗反应的预测标记物。 为了支持PPG研究人员的影像研究，我们建议建立一个非侵入性的生物成像核心 监测免疫反应。这一核心将补充最先进的体外免疫 核心A中描述的监测测量，并将使PPG调查人员能够深入临床前和 使用多种成像方式的临床“活体”免疫监测研究。 拟议的核心将利用功能和解剖方面的独特专业知识和基础设施 层析成像已经在加州大学洛杉矶分校提供，还将协调临床前成像实验 在其他参与机构演出。我们设想，成像核心将有助于巩固长期 涉及成像、基因治疗、基础和临床领域专家的互动式多机构协作 免疫学方面，处于癌症免疫治疗过渡期研究的前沿。

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.