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

摘要 这份提案描述了一项为期五年的职业发展计划，为候选人金振焕博士 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，提供更多的医学成像、细胞工程和 纳米材料。主要导师斯坦尼斯拉夫·埃米利亚诺夫博士(佐治亚理工学院BME教授) 在仪器、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 探员们。共同导师是夏尤南博士(佐治亚理工学院BME教授)，他拥有以下专业知识 纳米粒子和Gabriel Kuong博士(佐治亚理工学院BME副教授)，他在T 细胞工程学。金博士将与凯文·卡林斯基医学博士(Emory医学副教授)合作 研究乳腺癌肿瘤学，海顿·基西克博士(埃默里大学泌尿外科助理教授) Krishnendu Roy博士(佐治亚理工学院BME教授)研究T细胞制造。 在这项应用中，Kim博士将演示具有可调光学峰值的等离子纳米颗粒的使用 超声与光声(US/PA)联合成像的声学造影剂。已开发的 成像试剂和US/PA系统将用于图像引导的嵌合抗原受体(CAR)T细胞治疗 在乳腺癌和感应交付的CAR T细胞在肿瘤微环境(TME)的活动。当前 CAR T细胞治疗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是至关重要的 结果。通过用在近红外(NIR)光谱范围内吸收的金纳米棒(AuNRs)标记CAR T细胞， 该项目旨在能够跟踪输注后的CAR T细胞以进行图像引导治疗(目标1)。 实施US/PA成像技术将允许实时、高分辨率地检测CAR T细胞 在可靠的成像深度内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成像传感器选择性和灵敏地检测从 注射CAR T细胞将使监测CAR T细胞活动成为可能，从而评估和控制 具有额外外部刺激的微环境(目标3)。目标1和目标2(K99阶段)将在 来自具有广泛纳米技术培训的导师/合作导师的强大导师(夏又楠博士)， CAR T细胞工程(Gabriel Kuong，博士)和US/PA成像(Stanislav Emelianov，博士)。金博士将 独立执行拟议的目标3，并利用K99阶段收集的扩展专业知识。这个 在整体研究和职业培训过程中获得的多学科知识，该项目将提供 金博士基金会-R00阶段的独立研究员，开发高级应用程序 纳米技术在治疗癌症和其他疾病方面的创新治疗方法。

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.