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

项目总结 免疫抑制的肿瘤微环境给胰腺的治疗带来了巨大的挑战。 导管腺癌(PDAC)。它对“黄金标准”化疗和放射治疗的抵抗力 免疫检查点阻断，最近已被FDA批准用于其他癌症类型，是推动 开发治疗PDAC的新疗法。对治疗的不良反应被认为是由于缺乏 与深度免疫抑制相关的瘤内效应性T细胞，抗原不足 肿瘤血管的表现以及促结缔组织增生性压迫。最近，无创聚焦 超声(FUS)已成为一种免疫调节性癌症治疗方法，多项研究表明 超声治疗后转移瘤负担减轻。然而，缺乏关于以下方面的知识 这项非常新的技术的作用机理以及实现最佳超声参数 持续有效的免疫疗法的进步对临床甚至临床前的广泛应用构成了障碍。 使用。此外，与成像相关的技术困难，以及由此导致的精确治疗 胰腺肿瘤与超声相比，有复杂的临床前研究。在这里，我们建议对 免疫生物标记物对不同聚焦超声参数反应的变化 最佳的超声参数以及机理。治疗性超声将在消融性的、温和的 热疗、低强度辐射力和空化制度，有和没有微泡。我们的建议 研究将使用具有临床意义的原位胰腺癌小鼠模型以及多个肿块 基于细胞学的免疫表型分析。此外，我们还将使用新颖的实时高分辨率图像制导 治疗性FUS技术，实现精确的图像引导治疗。一旦我们评估了前景 声学参数，我们将测试治疗方案与免疫检查点阻断，以评估增加 在治疗效果上。这一努力将为超声-免疫联合治疗的最佳设计提供信息。 针对PDAC的战略。

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.