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

项目摘要 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， 免疫检查点阻断，最近被FDA批准用于其他癌症类型， 开发治疗PDAC的新疗法。对治疗反应不佳被认为是由于缺乏 肿瘤内效应T细胞，这与严重的免疫抑制，抗原不足 呈现以及结缔组织增生驱动的肿瘤脉管系统的压缩。近年来，非侵入性聚焦 超声波（FUS）已成为一种免疫调节癌症治疗方法，几项研究显示， 和超声治疗后转移性肿瘤负荷减少。然而，缺乏知识， 这种新技术的作用机制以及最佳超声参数， 持续有效的免疫治疗改进对临床或甚至广泛的临床前免疫治疗提出了障碍。 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。在这里，我们提出了一个严格的研究， 免疫学生物标志物响应于不同聚焦超声参数的变化， 最佳超声参数以及机理。治疗性超声将在消融、轻度 热疗、低强度辐射力和空化机制，有和没有微泡。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FUS技术，以实现精确的图像引导治疗。一旦我们评估了有希望的 声学参数，我们将测试免疫检查点阻断的治疗方案，以评估增加 在治疗效果上。这一努力将为联合超声-免疫治疗的最佳设计提供信息 针对PDAC的策略。

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.