Novel molecular imaging approaches to monitor gene and cell-based therapies

监测基因和细胞疗法的新型分子成像方法

• 批准号: 8161122
• 负责人: JOHANNES CZERNIN
• 金额: $ 65.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8161122
• 关键词: 2' -fluoro-5-methylarabinosyluracil; Academia; Acquired Immunodeficiency Syndrome; Address; Animal Model; Animals; Area; Basic Science; Biodistribution; Biopsy; Biopsy Specimen; Cancer Patient; Cardiovascular system; Cell Culture Techniques; Cell Therapy; Cell Transplants; Cells; Cellular Immunity; Cellular biology; Clinical; Colorectal Cancer; Communicable Diseases; Communities; Complement; Complex; Development; Disease; Drug Kinetics; Endocrine; Engineering; Evaluation; Gene Delivery; Gene Expression; Genes; Goals; Grant; Hematopoietic Stem Cell Transplantation; Home environment; Human; Image; Imaging technology; Immune response; Immunity; Immunotherapy; In Vitro; Industry; Insulin-Dependent Diabetes Mellitus; Integrase; Investigational Drugs; Investigational New Drug Application; Islet Cell; Laboratories; Lead; Life; Los Angeles; Malignant Neoplasms; Marketing; Medical; Medicine; Metastatic Neoplasm to the Liver; Modeling; Monitor; Mus; Myocardial dysfunction; Neurologic; New Drug Approvals; Organism; Outcome; Parkinson Disease; Patients; Phase; Physicians; Positron-Emission Tomography; Probability; Procedures; Proteins; Public Health; Radiochemistry; Regenerative Medicine; Reporter; Reporter Genes; Research; Research Personnel; Risk; Sampling Errors; San Francisco; Sensitivity and Specificity; Signal Transduction; Solutions; Staging; Stem cells; System; T-Lymphocyte; TK2 gene; Technology; Testing; Therapeutic; Time; Tissues; Variant; Viral Proteins; Work; base; cancer therapy; cancer type; clinical application; design; dosimetry; follow-up; gene therapy; genetically modified cells; healthy volunteer; human TK2 protein; immunogenic; immunogenicity; improved; in vivo; industry partner; melanoma; molecular imaging; mutant; nerve stem cell; novel; oncology; pre-clinical; preclinical evaluation; product development; research clinical testing; therapeutic gene; tool; vector

DESCRIPTION (provided by applicant): Novel molecular imaging approaches to monitor gene and cell-based therapies Gene and cell-based therapies have ushered in a new era of opportunities in regenerative medicine and oncology. However, a critical roadblock in the effective development and evaluation of cellular therapeutics is the inability to follow the fate and function of the therapeutic genes and cells in treated patients. We propose to develop technologies for specific identification and tracking of therapeutic genes and cells in vivo using positron emission tomography (PET), a quantitative, non-invasive molecular imaging approach applicable to both preclinical and clinical settings. This application addresses a key limitation of current reporter gene strategies, in which therapeutic vectors and cells are genetically modified to produce a signal detectable by PET. Instead of commonly used, highly immunogenic viral proteins, we will generate novel PET reporter genes based on fully human proteins, to overcome this challenge to clinical implementation. This project relies on many years of grants and basic research results that are now ready to advance to the commercial domain. We propose a three year effort to turn recent advances into practical outcomes delivered as end-user-ready PET Reporter Gene (PRG) delivery kits and PET Reporter Probes (PRP) that will enable whole body pharmacokinetic and therapeutic outcomes information. This application will also deliver preliminary information from a first-in-human Phase 0 small trial of new PET reporter probe biodistribution and dosimetry. Our proposal leverages an established partnership between UCLA (the laboratories of the Ahmanson Translational Imaging Division and the laboratory of Harvey Herschman) and CellSight Technologies (CST, a biotech company based in San Francisco, CA). The UCLA-CST partnership builds on past extensive interactions at UCLA between investigators and consultants, as described in this application. We will carry out four Specific Aims. Aim 1 consists of in vitro, cell culture and animal studies to evaluate and optimize new PET Reporter Gene-PET Reporter Probe (PRG-PRP) systems. Our new current PRG being developed is a point mutant (N44D) of the human thymidine kinase 2 (tk2) gene. L-[18F]FMAU and L- [18F]FEAU, two hTK2-N44D substrates, are our new PRPs. In Aim 1 we will also determine whether the TK2- based PRG can elicit an immune response in humans and we propose a strategy to eliminate this possibility. In Aim 2 we propose a stringent preclinical evaluation of the new PRG-PRP systems, using animal models of gene and cell-based therapies against two types of cancer: hepatic metastases of colorectal cancer and melanoma. Aim 3 proposes a strategy to develop, validate, and commercialize kits for PRG delivery into murine and human therapeutic cells and a plan to disseminate this new capability to wider communities of end- users. In Aim 4 we will complete an eIND submission to enable first-in-human studies of the biodistribution and dosimetry of the new PET reporter probes L-FMAU and L-FEAU. These "first-in-human" studies will set the stage for a follow-up study in which UCLA and CST will submit a full IND application to the FDA to initiate clinical testing of the new PRG-PRP systems in cancer patients. The set of new PET imaging technologies co-developed by UCLA and CST investigators may find immediate clinical applications in experimental gene and cell-based therapies in cancer and may be broadly applicable to therapies for diseases with significant public health impact, including transplantation of hematopoietic stem cells in congenital and acquired disorders such as AIDS, islet cells in type 1 diabetes, ES-derived neural stem cells in Parkinson's disease, and stem cells in myocardial dysfunction. PUBLIC HEALTH RELEVANCE: One of the great promises of cell-based therapies is that physicians will find a way to isolate and modify patient's stem cells or T lymphocytes so that they can be re-injected into patients to treat their disease. However, a key challenge is to be able to monitor the cells after they have been administered and see if they survive and engraft, whether they home to areas of disease, and whether they are able to reestablish the activity needed to counteract disease. We are developing novel tools to follow the fate and function of transplanted cells, based on a powerful medical camera called the PET scanner. PET imaging, or positron emission tomography, allows doctors to visualize the biology of cells in living organisms, including patients. The development of novel tools and technologies that will ultimately enable the routine use of PET for clinical monitoring of cell-based therapies in oncology and regenerative medicine represents a complex endeavor that exceeds the capabilities of a typical academic group and carries substantial risks for start-up biotech companies. In our opinion, the solution is an integrated approach in which academic and industry partners work together from the inception of the project, on both discovery and product development phases. The scientific yield from this work may lead to improved therapies for cancer, significantly impacting public health.

描述（由申请人提供）：监测基因和细胞疗法的新型分子成像方法基因和细胞疗法开创了再生医学和肿瘤学的机遇新时代。然而，有效开发和评估细胞疗法的一个关键障碍是无法跟踪治疗基因和细胞在治疗患者中的命运和功能。我们建议开发使用正电子发射断层扫描（PET）来特异性识别和跟踪体内治疗基因和细胞的技术，PET是一种适用于临床前和临床环境的定量、非侵入性分子成像方法。该应用解决了当前报告基因策略的一个关键限制，其中治疗载体和细胞经过基因改造以产生可通过 PET 检测的信号。我们将生成基于完全人类蛋白的新型 PET 报告基因，而不是常用的高免疫原性病毒蛋白，以克服临床实施的这一挑战。该项目依赖于多年的资助和基础研究成果，这些成果现已准备好进入商业领域。我们建议用三年时间将最新进展转化为实际成果，以最终用户就绪的 PET 报告基因 (PRG) 交付套件和 PET 报告探针 (PRP) 的形式提供，从而提供全身药代动力学和治疗结果信息。该应用程序还将提供新 PET 报告探针生物分布和剂量测定的首次人体 0 期小型试验的初步信息。我们的提案利用了 UCLA（Ahmanson 转化成像部门的实验室和 Harvey Herschman 实验室）和 CellSight Technologies（CST，一家位于加利福尼亚州旧金山的生物技术公司）之间建立的合作伙伴关系。 UCLA-CST 合作伙伴关系建立在过去 UCLA 研究者和顾问之间广泛互动的基础上，如本申请中所述。我们将实现四个具体目标。目标 1 包括体外、细胞培养和动物研究，以评估和优化新的 PET 报告基因-PET 报告探针 (PRG-PRP) 系统。我们目前正在开发的新 PRG 是人胸苷激酶 2 (tk2) 基因的点突变体 (N44D)。 L-[18F]FMAU 和 L-[18F]FEAU 这两种 hTK2-N44D 底物是我们的新 PRP。在目标 1 中，我们还将确定基于 TK2 的 PRG 是否可以在人类中引发免疫反应，并提出一种策略来消除这种可能性。在目标 2 中，我们提出对新的 PRG-PRP 系统进行严格的临床前评估，使用基因和细胞疗法的动物模型来对抗两种类型的癌症：结直肠癌和黑色素瘤的肝转移。目标 3 提出了一项开发、验证和商业化用于将 PRG 递送至小鼠和人类治疗细胞的试剂盒的策略，以及一项向更广泛的最终用户社区传播这种新功能的计划。在目标 4 中，我们将完成 eIND 提交，以便能够对新型 PET 报告探针 L-FMAU 和 L-FEAU 的生物分布和剂量测定进行首次人体研究。这些“首次人体”研究将为后续研究奠定基础，加州大学洛杉矶分校和 CST 将向 FDA 提交完整的 IND 申请，以启动癌症患者中新 PRG-PRP 系统的临床测试。由 UCLA 和 CST 研究人员共同开发的一套新 PET 成像技术可能会在癌症的实验基因和细胞疗法中找到直接的临床应用，并可能广泛适用于对公共健康产生重大影响的疾病的治疗，包括在先天性和后天性疾病（如艾滋病）中移植造血干细胞，在 1 型糖尿病中移植胰岛细胞，在 1 型糖尿病中移植 ES 衍生的神经干细胞。 帕金森病和心肌功能障碍中的干细胞。 公共健康相关性：基于细胞的疗法的一大前景是，医生将找到一种方法来分离和修饰患者的干细胞或 T 淋巴细胞，以便将它们重新注射到患者体内来治疗他们的疾病。然而，一个关键的挑战是能够在施用细胞后对其进行监测，看看它们是否存活和移植，它们是否驻留在疾病区域，以及它们是否能够重建抵抗疾病所需的活性。我们正在开发新的工具来跟踪移植细胞的命运和功能，基于强大的医疗相机（称为 PET 扫描仪）。 PET 成像或正电子发射断层扫描使医生能够可视化活体（包括患者）细胞的生物学特征。新型工具和技术的开发最终将使 PET 能够常规用于肿瘤学和再生医学中基于细胞的疗法的临床监测，这是一项复杂的工作，超出了典型学术团体的能力，并且给初创生物技术公司带来了巨大的风险。我们认为，该解决方案是一种综合方法，学术界和行业合作伙伴从项目一开始就在发现和产品开发阶段进行合作。这项工作的科学成果可能会改善癌症疗法，从而显着影响公众健康。