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.

项目概要免疫抑制性肿瘤微环境给胰腺癌的治疗带来了巨大的挑战导管腺癌（PDAC）对“金标准”化疗和放射治疗以及对免疫检查点阻断最近已被 FDA 批准用于其他癌症类型，这是开发治疗 PDAC 的新疗法治疗反应不佳被认为是由于缺乏瘤内效应 T 细胞，与深度免疫抑制、抗原不足相关最近，非侵入性聚焦于肿瘤血管系统的呈现以及结缔组织形成驱动的压缩。超声（FUS）已成为一种免疫调节癌症疗法，多项研究表明原发性然而，缺乏关于超声治疗后转移肿瘤负荷的认识。这种新技术的作用机制以及最佳超声参数以实现持续有效的免疫治疗改进对临床甚至广泛的临床前治疗构成了障碍此外，与成像相关的技术困难以及因此的精确治疗胰腺肿瘤的超声检查，有复杂的临床前研究，在这里，我们建议进行严格的研究。免疫生物标志物响应不同的聚焦超声参数而变化，以阐明两者最佳超声参数以及治疗超声机制将因消融性、轻度超声治疗而异。我们提出的热疗、低强度辐射力和空化机制，有或没有微泡。研究将使用具有临床意义的胰腺癌原位小鼠模型以及多重肿块此外，我们将使用新型实时高分辨率图像引导。一旦我们评估了前景，FUS 技术就能实现精确的图像引导治疗。声学参数，我们将测试免疫检查点封锁的治疗方案以评估增加这项工作将为联合超声免疫疗法的优化设计提供信息。针对 PDAC 的策略。