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

基本信息

批准号：
10861106
负责人：
Jinhwan Kim
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10861106
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 Collaborations Contrast Media DNA Detection Development Disease Doctor of Medicine Doctor of Philosophy Dose Engineering Exhibits Foundations Goals Granzyme Histologic Hydroquinones Image Imaging Techniques Imaging technology 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 Prediction of Response to Therapy 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 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 manufacture 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 tumor tumor immunology tumor microenvironment ultrasound

项目摘要

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.

概括该提案描述了一个为期五年的职业发展计划，旨在为候选人 Jinhwan Kim 博士做好准备：该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，提供医学成像、细胞工程和纳米材料的主要导师，Stanislav Emelianov 博士（佐治亚理工学院 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共同导师是 Younan Xia 博士（佐治亚理工学院 BME 教授），他在以下领域拥有丰富的专业知识：纳米粒子和 Gabriel Kwong 博士（佐治亚理工学院 BME 副教授），他在 T 方面的专业知识 Kim 博士将与医学博士 Kevin Kalinsky（埃默里大学医学副教授）合作大学）乳腺癌肿瘤学，Haydn Kissick 博士（埃默里大学泌尿科助理教授）癌症免疫学方面的研究，以及 T 细胞制造方面的 Krishnendu Roy 博士（佐治亚理工学院 BME 教授）的研究。在此应用中，Kim 博士将演示具有可调峰值光学的等离子体纳米颗粒的使用吸收作为超声和光声（US/PA）组合成像的造影剂。显像剂和US/PA系统将用于图像引导嵌合抗原受体（CAR）T细胞治疗在乳腺癌中检测并检测肿瘤微环境 (TME) 中递送的 CAR T 细胞的活性。 CAR T 细胞治疗方法缺乏监测输注 CAR T 细胞的位置和活性的能力实时，这对于了解 CAR T 细胞的生物学效应和预测治疗至关重要通过用吸收近红外 (NIR) 光谱范围的金纳米棒 (AuNR) 标记 CAR T 细胞，该项目旨在实现图像引导治疗输注后 CAR T 细胞的跟踪（目标 1）。实施 US/PA 成像技术将实现 CAR T 细胞的实时、高分辨率检测在可靠的成像深度中提供大量的解剖信息（目标 2）此外，黄金的设计。基于纳米颗粒的 US/PA 成像传感器，可选择性且灵敏地检测从注射的 CAR T 细胞将能够监测 CAR T 细胞的活性，评估从而控制具有额外外部刺激的微环境（目标 3）将在目标 1 和 2（K99 阶段）下进行指导。来自接受过广泛纳米技术培训的导师/共同导师的大力指导（夏佑南博士）， CAR T 细胞工程（Gabriel Kwong 博士）和 US/PA 成像（Stanislav Emelianov 博士）。利用 K99 阶段收集的扩展专业知识独立实施拟议的目标 3。在整体研究和职业培训中获得的多学科知识，该项目将提供 Kim 博士是 R00 阶段的独立研究员，为开发高级应用程序奠定了基础纳米技术用于治疗癌症和其他疾病的创新治疗方法。