Parametric optimization of ultrasound-mediated immuno-modulation for pancreatic cancer therapy

超声介导的胰腺癌免疫调节的参数优化

基本信息

批准号：
10375345
负责人：
Paul A Dayton
金额：
$ 10.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375345
关键词：
Ablation Acoustics Agitation Antibodies Antigen Presentation Antigens B-Lymphocytes Biological Blood Vessels CD8-Positive T-Lymphocytes Cells Clinic Clinical Coagulative necrosis Combination immunotherapy Communities Cytometry Data Dendritic Cells Diagnosis Diagnostic Imaging Diagnostic tests Disease Distant Metastasis Effectiveness Excision FDA approved Fibroid Tumor Focused Ultrasound Focused Ultrasound Therapy Gold Histology Hyperthermia Image Immune Immune checkpoint inhibitor Immune response Immunization Immunologic Markers Immunologics Immunophenotyping Immunosuppression Immunotherapeutic agent Immunotherapy Incidence Infiltration Infrastructure Innovative Therapy Investigation Knowledge Malignant Neoplasms Malignant neoplasm of pancreas Measures Mechanics Mediating Methods Microbubbles Microscopic Motivation Mus Myeloid Cells Nature Neoplasm Metastasis Operative Surgical Procedures Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Patients Primary Neoplasm Public Health Publishing Radiation Radiation therapy Recurrence Research Resectable Resistance Role Signal Transduction Survival Rate System T-Cell Proliferation T-Lymphocyte Technology Testing Therapeutic Therapeutic Effect Time Tissues Translations Treatment Efficacy Treatment Protocols Tumor Burden Tumor-infiltrating immune cells Ultrasonography United States Uterine Fibroids Variant Vascular Permeabilities Work Xenobiotics alternative treatment anti-CTLA4 anti-CTLA4 antibodies anti-PD-1 anti-PD1 therapy anti-tumor immune response base cancer therapy cancer type chemotherapeutic agent clinical translation design effective therapy effector T cell experience high resolution imaging image guided imaging modality immune checkpoint blockade immune health immunogenic immunoregulation improved insight intraperitoneal mouse model multiplex assay neoplastic cell new technology novel novel strategies novel therapeutics pancreatic cancer model pancreatic cancer patients pancreatic ductal adenocarcinoma model pancreatic neoplasm pre-clinical pre-clinical research preclinical study prevent response side effect skin damage sound standard of care trafficking treatment response tumor tumor microenvironment tumor-immune system interactions ultrasound

项目摘要

PROJECT SUMMARY The immunosuppressive tumor microenvironment creates a formidable challenge to treatment of pancreatic ductal adenocarcinoma (PDAC). Its resistance to the “gold standard” chemo- and radiation therapy and to immune checkpoint blockade, which has recently been FDA approved for other cancer types, is motivation for to develop new therapies for treating PDAC. Poor responses to therapy are thought to be due to paucity of intratumoral effector T cells, which correlates with profound immunosuppression, insufficient antigen presentation as well as desmoplasia-driven compression of tumor vasculature. Recently, non-invasive focused ultrasound (FUS) has emerged as an immunomodulatory cancer therapy, with several studies showing primary and metastatic tumor burden reduction after ultrasound treatment. However, lack of knowledge regarding mechanisms of action with this very new technology as well as optimal ultrasound parameters to achieve consistently effective immunotherapy improvement presents a barrier to clinical or even widespread preclinical use. Furthermore, technical difficulties associated with imaging and consequently, precise treatment of pancreatic tumors with ultrasound, have complicated preclinical studies. Here, we propose a rigorous study of immunological biomarker changes in response to varying focused ultrasound parameters to both elucidate optimal ultrasound parameters as well as mechanism. Therapeutic ultrasound will be varied across ablative, mild hyperthermia, low-intensity radiation force, and cavitation regimes, with and without microbubbles. Our proposed research will use clinically meaningful orthotopic murine models of pancreatic cancer as well as multiplex mass cytometry-based immuno-phenotyping. Furthermore, we will use novel real-time high-resolution image-guided therapeutic FUS technology to enable precise image guided treatment. Once we have evaluated promising acoustic parameters, we will test the treatment protocols with immune checkpoint blockade to evaluate increase in therapeutic efficacy. This effort will inform the optimal design of combined ultrasound-immunotherapy strategies against PDAC.

项目摘要免疫抑制性肿瘤微环境对胰腺治疗造成了巨大的挑战导管腺癌（PDAC）。它对“黄金标准”化学疗法的抵抗力以及对免疫检查点封锁最近已获得FDA批准其他癌症类型的封锁是动机开发用于治疗PDAC的新疗法。人们认为对治疗的反应不佳是由于很少肿瘤内效应T细胞与深刻的免疫抑制相关，抗原不足肿瘤脉管系统的表现以及脱木质驱动的压缩。最近，非侵入性集中超声（FUS）已成为一种免疫调节性癌症疗法，其中几项研究表明原发性疗法超声处理后的转移性肿瘤减少。但是，缺乏有关采用这种非常新技术以及最佳的超声参数来实现的动作机制一贯有效的免疫疗法改善呈现出临床甚至宽度临床前的障碍使用。此外，与成像相关的技术困难，因此，精确处理具有超声检查的胰腺肿瘤具有复杂的临床前研究。在这里，我们提出了一项严格的研究免疫生物标志物在响应不同的聚焦超声参数的响应中变化，以阐明最佳超声参数以及机制。治疗性超声将在消融中的中间高温，低强度辐射力和空化状态，有和没有微泡。我们提出的研究将使用临床上有意义的胰腺癌原位鼠模型以及多重质量基于细胞仪的免疫 - 表型。此外，我们将使用新颖的实时高分辨率图像引导治疗FUS技术可实现精确的图像指导治疗。一旦我们评估了承诺声学参数，我们将使用免疫检查点阻塞测试治疗方案，以评估增加在治疗有效性方面。这项工作将为联合超声免疫疗法的最佳设计提供信息针对PDAC的策略。