PET Imaging of Tumor Targeting & Role of T Lymphocytes

描述（由申请人提供）： 本提案的总体目标是开发用于T淋巴细胞过继转移用于抗肿瘤疫苗接种后的命运的重复非侵入性体内成像的方法。所提出的成像方法将允许回答与T细胞迁移和归巢到肿瘤靶点、其随后的活化和细胞溶解活性以及T细胞活力的持续时间相关的几个问题。所提出的成像方法的最终目的是评估肿瘤靶点的T细胞活化程度，评估肿瘤浸润T细胞的细胞毒性潜力，并在治疗期间早期预测其溶瘤疗效。我们提出将T细胞的遗传标记与多个报道基因结合联合收割机，然后重复施用短寿命放射性同位素报道探针，以用PET或其他成像技术顺序地对表达报道基因的细胞成像（即，荧光、生物发光、MRI）。具体而言，我们将探索用新的报告基因-报告探针组合和新的多报告基因构建体遗传标记T细胞的可行性。我们将使用[124 I]FIAU和新开发的短寿命放射性标记探针来测试一种新的报告基因，即截短的人线粒体胸苷激酶2型（hTK 2）的可行性，用于hTK 2 [2 '-18 F]FEAU和[11 C]FEAU的成像。我们计划开发几种双报告系统，其中hTK 2将组成型表达为“信标”报告基因，而突变型HSV 1-tk（HSV 1-sr 39 tk）基因（通过[18 F]FHBG成像）将以T细胞和激活特异性方式表达为“传感器”报告基因。所提出的多报告基因成像范例将在基于人工抗CEA或抗PSMA T细胞受体并分别用于治疗结直肠癌和前列腺癌的新型抗癌T细胞疫苗的评估和优化中实施。成像将用于在用各种细胞因子进行共刺激治疗之前和期间监测过继转移的T细胞的运输、定位和活化。这些研究将评估拟议的治疗和成像方法在临床环境中实施的可行性和适用性。

DESCRIPTION (provided by applicant): The overall aim of this proposal is to develop approaches for repetitive non-invasive in vivo imaging of the fate of T lymphocytes after their adoptive transfer for anti-tumor vaccination. The proposed imaging approaches will allow to answer several questions related to T-cell migration and homing to the tumor target, their subsequent activation and cytolytic activity, and the duration of T-cell viability. The ultimate aim of the proposed imaging approaches is to assess the degree of T cell activation at tumor target, to assess the cytolitic potential of tumor infiltrating T cells, and to predict their tumorolytic efficacy early on during therapy. We propose to combine the genetic labeling of T-cells with multiple reporter genes followed by the repetitive administration of short-lived radioisotope reporter probes to sequentially image the reporter gene expressing cells with PET or other imaging technologies (i.e., fluorescence, bioluminescence, MRI). Specifically, we will explore the feasibility of genetic labeling of T-cells with novel reporter gene - reporter probe combinations and novel multi-reporter gene constructs. We will test the feasibity of a novel reporter gene, the truncated human mitochondrial thymidine kinase type two (hTK2) using [124I]FIAU and newly developed short lived radiolabeled probes for imaging of hTK2 [2'-18F]FEAU and [11C]FEAU. We plan to develop several dual-reporter systems in which the hTK2 will be expressed constitutively as a "beacon" reporter gene and the mutant HSV1-tk (HSV1-sr39tk) gene (imaged by [18F]FHBG) will be expressed as "sensor" reporter gene in a T cell- and activation-specific manner. The proposed multi-reporter gene imaging paradigm will be implemented in the assessment and optimization of new anti-cancer T-cell vaccines that are based on the artificial anti-CEA or anti-PSMA T-cell receptors and used for treatment of colorectal and prostate carcinomas, respectively. Imaging will be used for monitoring the trafficking, localization and activation of adoptively transferred T cells before and during co-stimulatory therapy with various cytokines. These studies will assess the feasibility and applicability of the proposed therapeutic and imaging approaches for implementation in clinical setting.