CLINICAL TRANSLATION OF 19F MRI TO VISUALIZE CANCER IMMUNOTHERAPEUTIC CELLS

19F MRI 的临床转化使癌症免疫治疗细胞可视化

• 批准号: 7663569
• 负责人: ERIC T. AHRENS
• 金额: $ 49.21万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-10 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663569
• 关键词: Accounting; Address; Advanced Malignant Neoplasm; Animals; Apoptosis; Attenuated Vaccines; Biocompatible; Cancer Patient; Cell Count; Cell Therapy; Cell Transplants; Cell physiology; Cells; Cellular biology; Characteristics; Clinical; Clinical Research; Clinical Trials; Clinical effectiveness; Colon Carcinoma; Colorectal Cancer; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disabled Persons; Disease; Dose; Ensure; Excision; Human; Image; Imagery; Imaging Device; Imaging technology; Immune system; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Injection of therapeutic agent; Intervention; Label; Laboratories; Life; Magnetic Resonance Imaging; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Methods; Modeling; Monitor; Mus; Operative Surgical Procedures; Outcome; Outcome Measure; Patients; Pattern; Phenotype; Physiologic pulse; Pilot Projects; Population; Positioning Attribute; Procedures; Protocols documentation; Radiation; Reagent; Rectum; Research; Resectable; Residual Neoplasm; Rodent; Rodent Model; Route; Signal Transduction; Site; Surgical Oncology; Survival Rate; System; Technology; Therapeutic; Tissues; Translating; Translations; Tumor Antigens; United States; University of Pittsburgh Cancer Institute; Vaccination; Vaccines; base; cancer cell; cancer immunotherapy; cancer site; cancer therapy; cancer type; cell killing; cell motility; chemotherapy; cohort; design; experience; gastrointestinal; handicapping condition; improved; in vivo; innovation; insight; interest; killer T cell; lymph nodes; metastatic colorectal; migration; nanoparticle; novel; outcome forecast; patient population; perfluoropolyether; programs; public health relevance; response; safety study; tissue culture; tool; trafficking; translational study

DESCRIPTION (provided by applicant): We propose to translate a novel cellular MRI technology to visualize the trafficking of cellular therapeutics against colorectal cancer (CRC). CRC accounts for approximately 150,000 new cases annually, and 6,000 of these are treated every year at the University of Pittsburgh Cancer Institute (UPCI). CRC patients with resectable liver metastases constitute a group of patients with a unique combination of an overall poor prognosis and a 5-year overall survival rate between 20-35%, despite the presence of only minimal residual disease. Immunotherapeutic interventions may potentially be effective in this patient population. Currently, a major type of cell-based therapy used for CRC and other cancer types uses dendritic cells (DCs) as live vaccines that deliver tumor-specific antigens to the lymph nodes thereby inducing endogenous killer T cells (i.e., cytotoxic T cells or CTLs) in patients. To date, the inability to see the cells in vivo following therapeutic cell transfer is one of the greatest bottlenecks in the development of cancer immunotherapy. A commonly cited reason for the highly varied clinical outcomes of current DC-based vaccines is sub-optimal DC delivery to the lymph nodes. Recently, the laboratory of Dr. Ahrens has demonstrated a compelling technology that makes transplanted cells visible via MRI. In this approach, cells are labeled ex vivo with a novel perfluoropolyether (PFPE) nanoparticle composition and then introduced into the patient. Cell migration is subsequently monitored in vivo using 19F MRI. The key advantage of this approach is that the 19F images are extremely selective for the labeled cells, with no background signal from the host's tissues. Furthermore, accurate cell quantification in regions of interest is possible. Data show that PFPE nanoparticles are highly biocompatible inside cells. To date, several in vivo imaging studies have been conducted in rodent models. A clinical-grade version of the enabling PFPE nanoparticle reagent has recently been formulated and manufactured by Celsense, Inc. Celsense is currently performing mandatory in vitro and animal safety studies of this reagent for eventual human use. The proposed studies will allow us to simultaneously advance the technology of in vivo tracking of cell therapy in humans, while giving insights into ongoing clinical studies of immunotherapy in CRC, directed by Drs. Kalinski and Bartlett at the UPCI. The proposed project has three Specific Aims: (1a) Establish PFPE labeling protocols for therapeutic cells. We will develop optimal tissue culture protocols for PFPE labeling of immunotherapeutic DCs. (1b) Determine in vitro characteristics of therapeutic cells following labeling with PFPE. We will rigorously evaluate the degree to which PFPE labeling induces any alterations in DC function and phenotype in vitro. (2a,b) study cell trafficking and PFPE clearance of labeled DCs in a rodent model. (3a) Implementation of sensitive 19F MRI/MRS methods on a 3T clinical MRI system. We will optimize pulse sequences and evaluate the minimum detectable cell numbers using phantom studies. (3b) Pilot study tracking immunotherapeutic cells in CRC patients. We will amend the existing UPCI CRC therapeutic protocol (UPCI 05-063; BB-IND 13,234) to include imaging of transferred cells. In a small cohort of CRC patients (n=6), we will image the migration of DC-based vaccines to the lymph nodes. We will follow their administration by the traditional intradermal route and a novel intralymphatic route developed to accelerate the DC delivery to the lymph nodes and to protect booster doses of DCs from elimination by the previously-induced CTLs. The proposed translational studies are the first effort to evaluate the potential of 19F MRI/MRS-based cell tracking for clinical use. Additionally, we will garner preliminary data critically important for improving the immunotherapeutic strategies in metastatic CRC and other forms of cancer. The Pittsburgh region has exceptional strength in cancer immunotherapy and imaging innovations. We have organized a potent research team from the region to conduct this project. PUBLIC HEALTH RELEVANCE: In this proposal we will use advanced magnetic resonance imaging (MRI) technology to visualize the trafficking of cellular immunotherapy against colorectal cancer. Most often applied to advanced cancer, where existing therapies have limited efficacy, cellular immunotherapy is the administration of specialized cells that kill cancer cells or produce immunity to the disease. Immunotherapy is positioned to become a fourth strategy in cancer treatment supplementing surgery, chemotherapy, and radiation. Currently, the inability to see cells in the body following inoculation is one of the greatest bottlenecks in the development of cancer immunotherapy. This proposal will adapt modern imaging tools to address this urgent need, while giving insights into ongoing clinical studies of immunotherapy in colorectal cancer.

描述（由申请人提供）：我们建议翻译一种新的细胞MRI技术，以可视化针对结直肠癌（CRC）的细胞治疗剂的运输。CRC每年约有15万例新发病例，其中6,000例在匹兹堡大学癌症研究所（UPCI）接受治疗。具有可切除肝转移的CRC患者构成了一组具有总体不良预后和20- 35%的5年总体生存率的独特组合的患者，尽管仅存在微小的残留疾病。免疫干预可能对该患者人群有效。目前，用于CRC和其他癌症类型的主要类型的基于细胞的疗法使用树突状细胞（DC）作为活疫苗，其将肿瘤特异性抗原递送至淋巴结，从而诱导内源性杀伤T细胞（即，细胞毒性T细胞或CTL）。迄今为止，治疗性细胞转移后无法在体内看到细胞是癌症免疫治疗发展的最大瓶颈之一。当前基于DC的疫苗的高度变化的临床结果的一个通常引用的原因是次优的DC递送到淋巴结。最近，Ahrens博士的实验室展示了一种引人注目的技术，可以通过MRI看到移植的细胞。在这种方法中，细胞用新型全氟聚醚（PFPE）纳米颗粒组合物离体标记，然后引入患者体内。随后使用19 F MRI在体内监测细胞迁移。这种方法的主要优点是，19 F图像对标记的细胞具有极高的选择性，没有来自宿主组织的背景信号。此外，在感兴趣的区域中精确的细胞定量是可能的。数据显示，PFPE纳米颗粒在细胞内具有高度生物相容性。迄今为止，已经在啮齿动物模型中进行了几项体内成像研究。最近，Celsense，Inc.已经配制和制造了临床级版本的启用PFPE纳米颗粒试剂。Celsense目前正在对该试剂进行强制性体外和动物安全性研究，以便最终用于人体。拟议的研究将使我们能够同时推进人体细胞治疗的体内跟踪技术，同时深入了解正在进行的CRC免疫治疗临床研究，由UPCI的Kalinski和Bartlett博士指导。本项目有三个具体目标：（1）建立PFPE标记治疗细胞的方法。我们将开发最佳的组织培养方案PFPE标记的免疫球蛋白DCs。(1b)在用PFPE标记后确定治疗性细胞的体外特征。我们将严格评估PFPE标记在体外诱导DC功能和表型改变的程度。(2a，B）在啮齿动物模型中研究标记DC的细胞运输和PFPE清除。(3a)在3 T临床MRI系统上实现灵敏的19 F MRI/MRS方法。我们将优化脉冲序列，并使用体模研究评估最小可检测细胞数。(3b)跟踪CRC患者中免疫细胞的初步研究。我们将修改现有的UPCI CRC治疗方案（UPCI 05-063; BB-IND 13，234），以包括转移细胞的成像。在一小群CRC患者（n=6）中，我们将对基于DC的疫苗向淋巴结的迁移进行成像。我们将通过传统的皮内途径和一种新的淋巴管内途径进行给药，以加速DC向淋巴结的递送，并保护DC的加强剂量免受先前诱导的CTL的消除。拟议的转化研究是第一次尝试评估基于19 F MRI/MRS的细胞跟踪在临床应用中的潜力。此外，我们将收集对改善转移性CRC和其他形式癌症的免疫策略至关重要的初步数据。匹兹堡地区在癌症免疫治疗和成像创新方面具有非凡的优势。我们已经组织了一个来自该地区的强大研究团队来进行这个项目。公共卫生关系：在这项提案中，我们将使用先进的磁共振成像（MRI）技术来可视化细胞免疫治疗对结直肠癌的贩运。细胞免疫疗法最常应用于晚期癌症，其中现有疗法的疗效有限，细胞免疫疗法是给予杀死癌细胞或产生对疾病的免疫力的特化细胞。免疫疗法有望成为癌症治疗的第四种策略，补充手术，化疗和放疗。目前，接种后无法看到体内细胞是癌症免疫治疗发展的最大瓶颈之一。该提案将采用现代成像工具来解决这一紧迫需求，同时为正在进行的结直肠癌免疫治疗临床研究提供见解。