Focused Ultrasound and Multifunctional Nanoparticle Vaccines as Adjuvant Strategies for Cancer Immunotherapy

聚焦超声和多功能纳米颗粒疫苗作为癌症免疫治疗的辅助策略

基本信息

批准号：
10252068
负责人：
Natasha Diba Sheybani
金额：
$ 9.27万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-10-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252068
关键词：
Academic Training Acoustics Adjuvant Adoption Antigen Presentation Antigen-Presenting Cells Area Automobile Driving Award Benchmarking Biomedical Engineering Biopsy Blood Brain Bypass Cancer Research Project Cancer Vaccines Clinical Clinical Data Clinical Trials Complement Cross Presentation Dendritic Cells Deposition Development Doctor of Philosophy Drug Delivery Systems Drug Targeting Drug Transport Environment Evaluation Felis catus Focused Ultrasound Focused Ultrasound Therapy Foundations Gene Delivery Generations Genes Glioma Goals Human Immune Immune response Immunity Immunologics Immunomodulators Immunotherapeutic agent Immunotherapy Institution Investigational Therapies Laboratories Learning Lymphatic Malignant Neoplasms Malignant neoplasm of brain Mechanics Mediating Mentorship Metastatic Melanoma Metastatic breast cancer Methods Modeling Natural Immunity Outcome PD-1 blockade Patients Peptide Synthesis Peptides Peripheral Phase Polymers Population Positioning Attribute Postdoctoral Fellow Price Recording of previous events Regimen Research Research Personnel Research Project Grants Resistance Resources Role Site Solid Neoplasm Stimulus Surface System T-Lymphocyte Techniques Testing Therapeutic Therapeutic Uses Training Translating Translations Treatment Efficacy Tumor Antigens Tumor Immunity Tumor Specific Peptide Tumor Tissue Tumor-infiltrating immune cells Ultrasonography Universities Vaccines Virginia Work adaptive immunity anti-PD-1 anti-tumor immune response anticancer research base bench to bedside blood-brain tumor barrier cancer immunotherapy cancer vaccination career clinically relevant design effector T cell experience first-in-human immune checkpoint blockade immunogenicity immunoregulation insight malignant breast neoplasm nano nanocarrier nanoparticle novel novel strategies patient population pre-clinical precision medicine programs recruit resistance mechanism response systemic inflammatory response targeted treatment technological innovation tumor tumor microenvironment vaccination strategy

项目摘要

Project Summary/Abstract Cancer immunotherapy holds tremendous promise as a strategy for eradicating solid tumors. However, a poor T cell infiltration and persistence within the tumor microenvironment severely limits the accessibility of most immunotherapies to a broad patient population. There is an increasing demand for therapeutic platforms that boost the immunogenicity of tumors while curbing the onset of adaptive resistance mechanisms. This proposal sets forth a strategy for achieving this using allied approaches enabled by focused ultrasound (FUS) and synthetic nano-cancer vaccines. It is hypothesized that focused ultrasound (FUS) - a technique for non- invasive, non-ionizing perturbation of tumors using precisely targeted acoustic waves - can serve as an “auto- vaccination” strategy in solid tumors. During the F99 phase of this award, I propose to (i) ascertain the mechanisms by which spontaneous immunity against primary or disseminated tumors is elicited by FUS and (ii) apply this information to design and test immunotherapeutic approaches predicted to synergize with FUS. These studies will be performed across models of brain metastatic melanoma, glioma, and breast cancer. This framework is designed to permit insight into the distinct contributions of the brain and peripheral microenvironments to elicitation of anti-tumor immune responses with FUS. Our institution is well-positioned to conduct and translate FUS immune modulation research owing to the resources and strengths offered by its Focused Ultrasound Center and Human Immune Therapy Center. A significant capacity for bench-to-bedside translation is evidenced in this proposal, as pre-clinical findings in breast cancer will be benchmarked to human biopsies generated from an ongoing “first-in-human” clinical trial at University of Virginia (UVa) that combines FUS ablation with checkpoint blockade in metastatic breast cancer. I will complete this research under the mentorship of Dr. Richard Price (UVa Biomedical Engineering), whose lab boasts a strong history of research in the effective deployment of focused ultrasound for targeted drug and gene delivery to the brain. The F99 phase of this award aligns with the remaining 2 years of my tenure in the PhD program in Biomedical Engineering at UVa. In the K00 phase of this award, I will identify a postdoctoral institution with a strong cancer research program that will enable me to pursue a new, complementary avenue of training in the design and fabrication of personalized multifunctional nanoparticle-based vaccine systems. The two phases of this award will align to provide the foundation for establishment of an independent cancer research lab predicated on the use of therapeutic ultrasound and multifunctional nanoparticles as a platform for personalized cancer vaccination. The combination of these research areas significantly caters to the academic training, research experiences, and unique perspectives offered by my background as a biomedical engineer.

项目概要/摘要癌症免疫疗法作为根除实体瘤的策略具有巨大的前景。肿瘤微环境中 T 细胞浸润和持久性较差，严重限制了 T 细胞的可及性大多数免疫疗法适用于广大患者群体，对治疗平台的需求不断增加。增强肿瘤的免疫原性，同时抑制适应性耐药机制的发生。提案提出了使用聚焦超声（FUS）支持的联合方法来实现这一目标的策略聚焦超声（FUS）——一种非癌症治疗技术受到追捧。使用精确定位的声波对肿瘤进行侵入性、非电离扰动——可以作为“自动在该奖项的 F99 阶段，我建议 (i) 确定实体瘤的疫苗接种策略。 FUS 引发针对原发性或播散性肿瘤的自发免疫的机制，以及 (ii) 应用这些信息来设计和测试预计与 FUS 协同作用的免疫治疗方法。研究将针对脑转移性黑色素瘤、神经胶质瘤和乳腺癌模型进行。框架旨在允许深入了解大脑和外周的独特贡献我们的机构处于有利地位，可以通过 FUS 诱导抗肿瘤免疫反应。凭借其提供的资源和优势，开展和翻译 FUS 免疫调节研究聚焦超声中心和人体免疫治疗中心具有从实验室到临床的强大能力。该提案证明了转化，因为乳腺癌的临床前发现将以人类为基准弗吉尼亚大学 (UVa) 正在进行的“首次人体”临床试验产生的活检样本结合了 FUS 消融联合检查点阻断治疗转移性乳腺癌。我将在 Richard Price 博士（弗吉尼亚大学生物医学工程）的指导下完成这项研究，其实验室在有效部署聚焦超声用于靶向药物方面拥有悠久的研究历史该奖项的 F99 阶段与我剩余的 2 年任期相一致。在该奖项的 K00 阶段，我将确定一名博士后。拥有强大癌症研究项目的机构，这将使我能够追求新的、互补的途径个性化多功能纳米颗粒疫苗系统的设计和制造培训。该奖项的两个阶段将协调一致，为建立独立的癌症研究奠定基础实验室基于使用治疗性超声波和多功能纳米粒子作为平台这些研究领域的结合极大地迎合了学术界的需求。我作为生物医学工程师的背景提供了培训、研究经验和独特的视角。