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

• 批准号: 10092130
• 负责人: Paul A Dayton
• 金额: $ 10.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092130
• 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; tumor; tumor microenvironment; tumor-immune system interactions

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.

项目总结