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: 10225356
• 负责人: ERIC T. AHRENS
• 金额: $ 45.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225356
• 关键词: Adoption; Biodistribution; Biological Assay; Cell Count; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Cellular immunotherapy; Cessation of life; Chemotherapy and/or radiation; Clinical; Clinical Research; Clinical Trials; Culture Media; Data; Data Analyses; Dendritic Cells; Detection; Development; Dose; Emulsions; Fluorine; Fluorocarbons; Foundations; Funding; Future; Grant; Head and Neck Cancer; Homing; Human; Image; Imaging technology; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infusion procedures; Investments; Label; Leukocytes; Lymphocyte; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Methods; Modeling; Non-Invasive Cancer Detection; Operative Surgical Procedures; Outcome; PD-1 blockade; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Population; Prognosis; Protocols documentation; Rodent; Signal Transduction; Site; Solid Neoplasm; Speed; Surrogate Markers; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Translations; Treatment Efficacy; Tumor-Infiltrating Lymphocytes; United States; anti-cancer; base; blind; cancer diagnosis; cancer immunotherapeutics; cancer therapy; cell behavior; cellular engineering; cellular imaging; clinical translation; cohort; colon cancer patients; design; dosage; efficacious treatment; fight against; head and neck cancer patient; imaging agent; imaging probe; in vivo; innovation; insight; interest; lymphocyte trafficking; man; melanoma; novel; novel therapeutics; patient derived xenograft model; pilot trial; programmed cell death protein 1; repaired; responders and non-responders; therapy development; tissue culture; trafficking; tumor; tumor growth; tumor infiltrating lymphocyte therapy; tumor xenograft

In this renewal application, we propose to use a novel cellular magnetic resonance imaging (MRI) technology to visualize the trafficking of tumor infiltrating lymphocytes (TILs) in head and neck cancer (HNC) patients. In the first funding cycle, we successfully developed and implemented ‘first-into-man’ clinical translation of a disruptive imaging technology based on a novel perfluorocarbon (PFC) emulsion probe (CS-1000) that employs fluorine- 19 (19F) MRI cell detection. Overall, cell populations of interest are intracellularly-labeled in culture using non- toxic PFC as an additive to the culture media. Following transfer to the subject, cells are tracked in vivo using 19F MRI. The fluorine inside the cells yields cell-specific images, with no background signal. Images are quantified to measure apparent cell numbers at sites of accumulation. In the pilot trial, immunotherapeutic dendritic cells (DCs) were labeled with CS-1000 and longitudinally detected in colorectal cancer patients using 19F MRI. Building on these efforts, we aim to use this technology for imaging TILs in HNC. HNC is the sixth most common cancer worldwide. In the United States, HNC accounts for 3% of all cancers diagnosed annually and 2% of cancer- related deaths, with poor prognosis (<2 mo survival) after reoccurrence. Immunotherapy is emerging as a key anti-cancer strategy with the potential to provide patient-specific, less toxic and more efficacious treatments. TILs have proven successful in melanoma, and a major effort is underway at UCSD to develop this therapy for HNC. Although TIL therapies have been used in hundreds of patients to date, fundamental questions remain about tumor homing and cell survival of TILs in vivo. Up until now, we have been blind to the behavior of cells after infusion into patients. Importantly, TIL trafficking, as well as cell survival, may be predictive of responders versus non-responders to treatment. Imaging could provide real-time surrogate markers to gauge TIL tumor homing capacity and TIL survival in each patient, which could better inform therapeutic design, as well as post-trial data analysis. The proposal has three Specific Aims: AIM 1: PFC labeling for TILs. (a) We will develop tissue culture protocols for PFC labeling of clinical TIL batches at clinical scale (>1×109 cells). (b) We will rigorously evaluate the degree to which PFC labeling induces potential alterations in TIL viability and phenotype in vitro. AIM 2: In vivo rodent studies to evaluate biodistribution of TILs. Using a human patient-derived xenograft (PDX) tumor model for HNC, we will evaluate the tumor homing ability and overall biodistribution of CS-1000 labeled TILs (CS-TILs) with and without co-administration of PD-1 blockade. We will test the hypothesis that PD-1 co- administration results in increased tumor homing and accumulation. AIM 3: Clinical CS-TILs in HNC patients. In two clinical trial HNC patient cohorts, we will evaluate the feasibility of using MRI to detect (A) conventionally administered CS-TILs and (B) CS-TILs administered in combination with PD-1 blockade. The 19F MRI will be used to assay putative CS-TIL tumor homing and survival in a longitudinal fashion. Overall, this study will help expand the use of 19F MRI to a wide range of clinical trials involving T cells and other types of leukocytes.

在此更新应用中，我们建议使用一种新颖的细胞磁共振成像（MRI）技术来 可视化头颈癌 (HNC) 患者中肿瘤浸润淋巴细胞 (TIL) 的运输。在 在第一个融资周期中，我们成功开发并实施了颠覆性药物的“首次进入人体”临床转化 基于新型全氟化碳 (PFC) 乳剂探头 (CS-1000) 的成像技术，该探头采用氟 19(19F)MRI细胞检测。总体而言，使用非细胞内标记培养物中感兴趣的细胞群 有毒的 PFC 作为培养基的添加剂。转移至受试者后，使用以下方法在体内追踪细胞 19F 核磁共振成像。细胞内的氟产生细胞特异性图像，没有背景信号。图像被量化 测量积累位点的表观细胞数。在试点试验中，免疫治疗树突状细胞 (DC) 用 CS-1000 标记，并使用 19F MRI 在结直肠癌患者中进行纵向检测。建筑 在这些努力中，我们的目标是使用该技术对 HNC 中的 TIL 进行成像。 HNC 是第六大常见癌症 全世界。在美国，HNC 占每年诊断出的所有癌症的 3%，占癌症的 2%。 相关死亡，复发后预后不良（<2 个月生存）。免疫疗法正在成为关键 抗癌策略有可能为患者提供特异性、毒性较小且更有效的治疗方法。 TIL 已被证明在黑色素瘤方面取得了成功，加州大学圣地亚哥分校 (UCSD) 正在大力开发这种治疗 HNC 的疗法。 尽管迄今为止 TIL 疗法已在数百名患者中使用，但基本问题仍然存在 TIL 的体内肿瘤归巢和细胞存活。到目前为止，我们对细胞的行为视而不见。 输注给患者。重要的是，TIL 运输以及细胞存活率可以预测反应者与 对治疗无反应者。成像可以提供实时替代标记来测量 TIL 肿瘤归巢 每个患者的能力和 TIL 生存率，这可以更好地为治疗设计以及试验后数据提供信息 分析。该提案具有三个具体目标： 目标 1：TIL 的 PFC 标签。 (a) 我们将发展组织培养 临床规模（>1×109 个细胞）临床 TIL 批次的 PFC 标记协议。 (b) 我们将严格评估 PFC 标记在体外诱导 TIL 活力和表型潜在改变的程度。目标 2：在 用于评估 TIL 生物分布的体内啮齿动物研究。使用人类患者来源的异种移植（PDX）肿瘤 HNC 模型，我们将评估 CS-1000 标记的 TIL 的肿瘤归巢能力和整体生物分布 (CS-TIL) 联合或不联合使用 PD-1 阻断剂。我们将检验 PD-1 协同作用的假设 给药导致肿瘤归巢和积累增加。目标 3：HNC 患者的临床 CS-TIL。 在两个临床试验 HNC 患者队列中，我们将评估使用 MRI 常规检测 (A) 的可行性 施用的 CS-TIL 和 (B) 与 PD-1 阻断联合施用的 CS-TIL。 19F MRI 将 用于纵向分析假定的 CS-TIL 肿瘤归巢和存活。总的来说，这项研究将有助于 将 19F MRI 的使用扩展到涉及 T 细胞和其他类型白细胞的广泛临床试验。

项目成果

Automated detection and characterization of SPIO-labeled cells and capsules using magnetic field perturbations.

• DOI: 10.1002/mrm.22998
• 发表时间: 2012-01
• 期刊: MAGNETIC RESONANCE IN MEDICINE
• 影响因子: 3.3
• 作者: Mills, Parker H.;Hitchens, T. Kevin;Foley, Lesley M.;Link, Thomas;Ye, Qing;Weiss, Clifford R.;Thompson, Joe D.;Gilson, Wesley D.;Arepally, Aravind;Melick, John A.;Kochanek, Patrick M.;Ho, Chien;Bulte, Jeff W. M.;Ahrens, Eric T.
• 通讯作者: Ahrens, Eric T.

IL-18-based combinatorial adjuvants promote the intranodal production of CCL19 by NK cells and dendritic cells of cancer patients.

• DOI: 10.4161/onci.26245
• 发表时间: 2013-09-01
• 期刊: Oncoimmunology
• 影响因子: 7.2
• 作者: Wong JL;Muthuswamy R;Bartlett DL;Kalinski P
• 通讯作者: Kalinski P

Metallofluorocarbon Nanoemulsion for Inflammatory Macrophage Detection via PET and MRI.

通过 PET 和 MRI 检测炎症巨噬细胞的金属氟碳纳米乳剂。

• DOI: 10.2967/jnumed.120.255273
• 发表时间: 2021
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Wang,Chao;Leach,BenjaminI;Lister,Deanne;Adams,StephenR;Xu,Hongyan;Hoh,Carl;McConville,Patrick;Zhang,Jing;Messer,Karen;Ahrens,EricT
• 通讯作者: Ahrens,EricT

Assaying macrophage activity in a murine model of inflammatory bowel disease using fluorine-19 MRI.

• DOI: 10.1038/labinvest.2012.7
• 发表时间: 2012-04
• 期刊: Laboratory investigation; a journal of technical methods and pathology

Combining perfluorocarbon and superparamagnetic iron-oxide cell labeling for improved and expanded applications of cellular MRI.

• DOI: 10.1002/mrm.25120
• 发表时间: 2015-01
• 期刊: MAGNETIC RESONANCE IN MEDICINE
• 影响因子: 3.3
• 作者: Hitchens, T. Kevin;Liu, Li;Foley, Lesley M.;Simplaceanu, Virgil;Ahrens, Eric T.;Ho, Chien
• 通讯作者: Ho, Chien