PET Imaging of Tumor Targeting & Role of T Lymphocytes

肿瘤靶向的 PET 成像

基本信息

批准号：
7348436
负责人：
Vladimir Ponomarev
金额：
$ 34.19万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-16 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7348436
关键词：
Address Adoptive Transfer Affinity Animals Applications Grants Arabinose Biological Bioluminescence Biopsy Blood specimen Cell Survival Cell Therapy Cells Clinical Colon Colorectal Coupled Development Doctor of Medicine Doctor of Philosophy Dose Enzymes Fluorescence Gene Expression Genes Genetic Genus Cola Homing Human Image Imaging technology In Vitro Invasive Investigational Therapies Label Life Magnetic Resonance Imaging Malignant Neoplasms Methods Mitochondria Monitor Phosphorylation Physiological Positron-Emission Tomography Prostate carcinoma Radioisotopes Radiolabeled Reporter Reporter Genes Research Personnel Retroviral Vector Role System T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Thymidine Kinase Vaccination Vaccines analog base cell motility clinically relevant cytokine imaging probe immune function in vivo mutant non-invasive monitor novel nucleoside analog radiotracer receptor sensor subcutaneous trafficking tumor tumor xenograft whole body imaging

项目摘要

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.

描述（由申请人提供）：该提案的总体目的是开发用于对T淋巴细胞命运的重复性非侵入性体内化学成像的方法，用于抗肿瘤疫苗接种。所提出的成像方法将允许回答与T细胞迁移和归因于肿瘤靶标有关的几个问题，其随后的激活和细胞溶解活性以及T细胞生存能力的持续时间。所提出的成像方法的最终目的是评估肿瘤靶标T细胞激活的程度，评估肿瘤浸润T细胞的细胞智能，并在治疗期间早期预测其肿瘤效应。我们建议将T细胞的遗传标记与多个报告基因相结合，然后重复施用短寿命的放射性同位素报告基因探针，以依次地图像用PET或其他成像技术表达细胞的报告基因（即荧光，生物发光，MRI，MRI）。具体而言，我们将探索具有新的报告基因 - 报告基因组合和新型多重孢子基因构建体的T细胞遗传标记的可行性。我们将使用[124i] FIAU和新开发的短期射线光明探针进行HTK2 [2'-18F] Feau和[11C] Feau的成像，测试新的记者基因的可行性，即截短的人类线粒体胸苷激酶2型（HTK2）（HTK2）。我们计划开发几种双重重复蛋白系统，其中HTK2将以“信标”记者的基因和突变的HSV1-TK（HSV1-SR39TK）基因（由[18F] FHBG成像成像）表示为“传感器”记者基因在T型细胞和激活标语中表示。所提出的多重孢子基因成像范式将在基于人工抗CEA或抗PSMA T细胞受体的新抗癌T细胞疫苗的评估和优化中实施，并分别用于结直肠癌和前列腺癌。成像将用于监测与各种细胞因子共刺激治疗之前和期间的运输，定位和激活。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。