Biological Imaging Core

摘要：新的过继性T细胞疗法已经在相当大比例的转移性黑色素瘤患者中实现了持久的客观临床应答。通过对淋巴细胞进行离体遗传修饰，允许产生大量具有增强的抗肿瘤功能的细胞，可以进一步提高治疗功效和可用性。这种过继性细胞转移免疫疗法的发展严重依赖于跟踪黑色素瘤患者移植后遗传修饰的淋巴细胞分布的工具的可用性。项目资助（PPG）研究人员在癌症动物模型和人类中的工作表明，这一目标可以通过使用新的分子成像技术（如正电子发射断层扫描（PET））来实现。 为了可视化移植到黑素瘤患者中的遗传修饰的T淋巴细胞和造血干细胞的分布，这些细胞将被工程化以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”广泛用于临床试验，并对PET探针（9-[4-[（18）F]氟-3-（羟甲基）-丁基]鸟嘌呤）（9（18 F]FHBG）具有非常高的亲和力。以痕量施用的[9（18）F]FHBG在表达HSVI-tk的细胞中特异性积累，并且所产生的信号可以通过PET检测。我们将使用这种技术在体内“计数”基因， 在全身不同部位的修饰细胞，包括淋巴器官和转移性黑色素瘤 存款这样的测量不能使用常规技术来执行，并且可以提供早期测量。 治疗反应的预测标志物。 为了支持PPG研究者的成像研究，我们建议建立一个生物成像核心， 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，并使PPG研究者能够进行临床前和 使用多种成像模式的临床“体内”免疫监测研究。 拟议的核心将利用独特的专业知识和基础设施， 断层成像已经在加州大学洛杉矶分校，也将协调临床前成像实验 在其他参与机构进行。我们设想，成像核心将有助于巩固长期的 互动的多机构合作，包括成像，基因治疗，基础和临床 免疫学，谁是在癌症免疫治疗过渡研究的前沿。

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.