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型的细胞MRI技术，以可视化针对大肠癌（CRC）的细胞疗法的运输。 CRC每年约有15万个新病例，其中6,000例在匹兹堡大学癌症研究所（UPCI）进行治疗。可切除肝转移的CRC患者构成了一群患者，尽管仅存在最小的残留疾病，但总体预后较差和5年总生存率的独特组合在20-35％之间。免疫治疗干预措施可能在该患者人群中有效。目前，用于CRC和其他癌症类型的主要基于细胞的疗法将树突状细胞（DC）用作活疫苗，可在患者中诱导内源性杀伤性T细胞（即细胞毒素T细胞或CTL），从而将肿瘤特异性抗原传递到淋巴结中。迄今为止，无法看到治疗细胞转移后体内细胞是癌症免疫疗法发展中最大的瓶颈之一。当前基于DC的疫苗高度多样的临床结果的普遍原因是向淋巴结的次级DC递送。最近，Ahrens博士的实验室展示了一种引人入胜的技术，该技术使移植的细胞可通过MRI看到。在这种方法中，将细胞用新型的全氟球菌（PFPE）纳米颗粒组成标记，然后引入患者。随后使用19F MRI在体内监测细胞迁移。这种方法的主要优点是，19F图像对于标记的细胞具有极高的选择性，没有宿主组织的背景信号。此外，可以在目标区域中准确的细胞定量。数据表明，PFPE纳米颗粒在细胞内部高度生物相容性。迄今为止，在啮齿动物模型中已经进行了几项体内成像研究。 Celsense，Incessene目前正在对该试剂进行强制性的体外和动物安全研究，以最终的人使用。拟议的研究将使我们能够同时推进人类体内细胞疗法的体内跟踪技术，同时洞悉由DRS指导的CRC中正在进行的CRC免疫疗法的临床研究。 Kalinski和Bartlett在UPCI。拟议的项目具有三个特定的目的：（1A）为治疗细胞建立PFPE标记方案。我们将开发用于免疫治疗DC的PFPE标记的最佳组织培养方案。 （1B）用PFPE标记后确定治疗细胞的体外特征。我们将严格评估PFPE标记在体外诱导DC功能和表型的任何变化的程度。 （2a，b）研究啮齿动物模型中标记的DC的细胞运输和PFPE清除率。 （3a）在3T临床MRI系统上实施敏感的19F MRI/MRS方法。我们将使用幻影研究优化脉冲序列并评估可检测到的最小细胞数量。 （3B）试验跟踪CRC患者的免疫治疗细胞。我们将修改现有的UPCI CRC治疗方案（UPCI 05-063; BB-IND 13,234），以包括转移的细胞的成像。在一小部分CRC患者（n = 6）中，我们将对基于DC的疫苗迁移到淋巴结的迁移。我们将按照传统的皮内途径和一条新型的膜内途径遵循他们的给药，以加速直流向淋巴结的递送，并保护DC的助推器剂量免受先前诱导的CTL的消除。拟议的翻译研究是评估19F MRI/基于MRS的细胞跟踪的潜力以进行临床使用的第一个努力。此外，我们将获得对改善转移性CRC和其他形式癌症的免疫治疗策略至关重要的初步数据。匹兹堡地区在癌症免疫疗法和成像创新方面具有出色的力量。我们已经组织了一个来自该地区的有力研究团队来进行该项目。公共卫生相关性：在此提案中，我们将使用先进的磁共振成像（MRI）技术来可视化对大肠癌的细胞免疫疗法的贩运。最常应用于晚期癌症，现有疗法的功效有限，细胞免疫疗法是杀死癌细胞或对疾病的免疫的专门细胞的给药。免疫疗法将成为补充手术，化学疗法和放射线的癌症治疗方面的第四个策略。目前，接种后无法看到体内细胞是癌症免疫疗法发展中最大的瓶颈之一。该提案将适应现代成像工具，以满足这种迫切需求，同时洞悉近直肠癌免疫疗法的临床研究。