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）。它对“金标准”化疗和放疗的抵抗力以及 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。对治疗的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 呈现以及结缔组织增生驱动的肿瘤脉管系统压缩。最近，非侵入性的重点 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 超声治疗后转移性肿瘤负荷减少。然而，缺乏相关知识 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 使用。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。在此，我们建议进行一项严格的研究 免疫生物标志物响应不同的聚焦超声参数而变化，以阐明 最佳超声参数和机制。超声治疗将根据消融性、轻度 热疗、低强度辐射力和空化状态，有或没有微泡。我们提出的 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 基于细胞计数的免疫表型分析。此外，我们将使用新颖的实时高分辨率图像引导 治疗性 FUS 技术可实现精确的图像引导治疗。一旦我们评估了有前途的 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 在治疗功效上。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。