Nanoparticle-augmented image-guided CAR T therapy and post-treatment assessment

纳米粒子增强图像引导的 CAR T 治疗和治疗后评估

• 批准号: 10449425
• 负责人: Jinhwan Kim
• 金额: $ 13.32万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449425
• 关键词: Ablation; Address; Adverse effects; Aftercare; Algorithms; Anatomy; Animals; Binding; Biological; Biological Markers; Biological Process; Biosensor; Blood flow; Breast Cancer Model; CAR T cell therapy; Cell Survival; Cell physiology; Cell surface; Cells; Clinical; Contrast Media; DNA; Detection; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Engineering; Exhibits; Foundations; Goals; Gold; Granzyme; Histologic; Hydroquinones; Image; Imaging Techniques; Immune; Immunotherapeutic agent; In Vitro; Infiltration; Infusion procedures; Interferon Type II; Interleukin-2; Interleukin-6; Knowledge; Label; Lasers; Life; Location; Maleimides; Malignant Neoplasms; Medical Imaging; Medicine; Mentors; Mentorship; Methods; Modification; Monitor; Nanosphere; Nanotechnology; Oncology; Optics; Oxygen; Phase; Physiologic pulse; Precision therapeutics; Program Development; Reaction Time; Research; Research Personnel; Resolution; Scientist; Signal Transduction; Site; Solid Neoplasm; Sulfhydryl Compounds; Surface; System; T-Lymphocyte; Therapeutic; Time; Tissues; Training; Translating; Translations; Treatment outcome; Ultrasonography; Universities; Urology; absorption; aptamer; base; cancer immunotherapy; cancer type; career; career development; cell behavior; cellular engineering; cellular imaging; chimeric antigen receptor; chimeric antigen receptor T cells; contrast imaging; cytokine; cytokine release syndrome; design; engineered T cells; experimental study; image guided; image guided therapy; imaging agent; imaging system; improved; in vivo; innovation; instrumentation; leukemia; malignant breast neoplasm; mid-career faculty; miniaturize; mouse model; multidisciplinary; nanoGold; nanobiomaterial; nanomaterials; nanoparticle; nanorod; nanosensors; neurotoxicity; photoacoustic imaging; plasmonics; preservation; prevent; professor; programs; remote control; remote sensing; response; sensor; side effect; therapy outcome; training project; tumor; tumor immunology; tumor microenvironment; ultrasound

SUMMARY This proposal describes a five-year career development program to prepare the candidate, Dr. Jinhwan Kim, for a career as an independent investigator. This program will build on Dr. Kim’s background as a material scientist and nanobiomaterial engineer by providing additional expertise in medical imaging, cell engineering, and nanomaterials. The primary mentor, Stanislav Emelianov, Ph.D. (Professor of BME at Georgia Tech), has expertise in instrumentation, imaging systems and algorithms, image-guided therapy, and imaging contrast agents. Co-mentors are Younan Xia, Ph.D. (Professor of BME at Georgia Tech), who has expertise in nanoparticles and Gabriel Kwong, Ph.D. (Associate Professor of BME at Georgia Tech), whose expertise in T cell engineering. Dr. Kim will collaborate with Kevin Kalinsky, M.D. (Associate Professor of Medicine at Emory University) on breast cancer oncology, Haydn Kissick, Ph.D. (Assistant Professor of Urology at Emory University) on cancer immunology, and Krishnendu Roy, Ph.D. (Professor of BME at Georgia Tech) on T cell manufacturing. In this application, Dr. Kim will demonstrate the use of plasmonic nanoparticles with tunable peak optical absorption as contrast agents for the combined ultrasound and photoacoustic (US/PA) imaging. The developed imaging agents and US/PA system will be used for image-guided chimeric antigen receptor (CAR) T cell therapy in breast cancer and sensing the activity of delivered CAR T cells in the tumor microenvironment (TME). Current approaches in CAR T cell therapy lack the ability to monitor the location and activity of the infused CAR T cells in real-time, which is critical to understand the biological effect of CAR T cells and to predict the treatment outcome. By labeling CAR T cells with gold nanorods (AuNRs) absorbing in near-infrared (NIR) spectral range, this project aims to enable tracking of the CAR T cells after infusion for image-guided therapy (Aim 1). Implementing the US/PA imaging technique will allow the real-time, high-resolution detection of the CAR T cells with great anatomical information in reliable imaging depth (Aim 2). Furthermore, the design of the gold nanoparticle-based US/PA imaging sensors that selectively and sensitively detect cytokines released from injected CAR T cells will enable monitoring CAR T cell activity, thereby assessing and controlling the microenvironment with additional external stimulation (Aim 3). Aims 1 and 2 (K99 phase) will be guided under the strong mentorship from mentor/co-mentors with extensive training on nanotechnology (Younan Xia, Ph.D.), CAR T cell engineering (Gabriel Kwong, Ph.D.), and US/PA imaging (Stanislav Emelianov, Ph.D.). Dr. Kim will independently conduct the proposed aim 3 with the extended expertise gathered during the K99 phase. The multidisciplinary knowledge gained during the overall research and career training, this project will provide a foundation for Dr. Kim – an independent investigator in the R00 phase, to develop advanced applications of nanotechnology in innovative therapeutic approaches to treat cancer and other diseases.

总结 本建议书描述了一个为期五年的职业发展计划，以帮助候选人Jinhwan Kim博士为 独立调查员的职业生涯这个项目将建立在金博士作为材料科学家的背景之上 和纳米生物材料工程师提供额外的专业知识，在医学成像，细胞工程， 纳米材料主要导师Stanislav Emelianov博士（格鲁吉亚理工学院BME教授）， 仪器、成像系统和算法、图像引导治疗和成像对比度方面的专业知识 剂.共同导师是夏友南博士。（格鲁吉亚理工学院BME教授），他在以下方面拥有专业知识： 纳米颗粒和Gabriel Kwong博士（格鲁吉亚理工学院BME副教授），他在T 细胞工程Kim博士将与Kevin Kalinsky博士合作。（埃默里大学医学副教授） 海顿·基西克（Haydn Kissick），博士。（埃默里大学泌尿外科助理教授） Krishnendu Roy，Ph.D.（格鲁吉亚理工学院BME教授）在T细胞制造方面的研究。 在这个应用中，Kim博士将演示使用具有可调峰值光学特性的等离子体纳米粒子。 作为用于组合超声和光声（US/PA）成像的造影剂，发达 成像剂和US/PA系统将用于图像引导的嵌合抗原受体（CAR）T细胞治疗 在乳腺癌中，并感测肿瘤微环境（TME）中递送的CAR T细胞的活性。电流 CAR-T细胞疗法中的方法缺乏监测输注的CAR-T细胞的位置和活性的能力 这对于了解CAR T细胞的生物学效应和预测治疗至关重要。 结果。通过用在近红外（NIR）光谱范围内吸收的金纳米棒（AuNR）标记CAR T细胞， 该项目旨在实现在输注后跟踪CAR T细胞以进行图像引导治疗（Aim 1）。 实施US/PA成像技术将允许实时，高分辨率检测CAR T细胞 在可靠的成像深度中具有丰富的解剖信息（目标2）。此外，黄金的设计 基于纳米颗粒的US/PA成像传感器，其选择性地和灵敏地检测细胞因子释放， 注射的CAR T细胞将能够监测CAR T细胞活性，从而评估和控制CAR T细胞的活性。 微环境与额外的外部刺激（目标3）。目标1和2（K99阶段）将在 来自导师/共同导师的强有力的指导，在纳米技术方面进行了广泛的培训（Youan Xia，博士）， CAR T细胞工程（Gabriel Kwong，Ph.D.），和US/PA成像（Stanislav Emelianov，Ph.D.）。金博士会 利用K99阶段积累的专业知识，独立实施拟议的目标3。的 在整个研究和职业培训过程中获得的多学科知识，该项目将提供一个 金博士的基金会-R 00阶段的独立研究员，开发先进的应用程序， 纳米技术用于治疗癌症和其他疾病的创新治疗方法。