An image-guided immunotherapy and hyperthermia delivery device to overcome barriers to tumor immunity for advanced hepatocellular carcinoma

摘要 肝细胞癌是美国与癌症相关的死亡中增长最快的原因。 免疫疗法是一种很有前途的治疗肝癌的新方法，但仍存在许多障碍。 肝细胞癌的免疫治疗。局部瘤内注射免疫疗法是克服 这些障碍，特别是考虑到局部免疫激活可以推动全身肿瘤免疫的事实。 然而，关于免疫疗法在肿瘤内的应用还存在很大的知识空白。 当通过传统的针头输送时，注射的药物会沿着针道移动并泄漏出去。 进入周围的正常组织。这不仅降低了治疗效果，也降低了治疗效果。 交付，但它也增加了全身毒性。此外，即使局部沉积了免疫疗法， 持续的微环境屏障可以抑制肿瘤免疫的产生。此应用程序将 对一种具有可调节的电绝缘套筒的新型肿瘤内给药系统进行专门评估 专为瘤内免疫治疗而设计(ImFusion系统)。除了受控交付之外， 对于注射的药物，ImFusion还允许射频介导的肿瘤内热疗产生。 初步数据显示，ImFusion系统导致肿瘤内药物的实质性改善 相对于传统的针头，它的热疗能力可以为肿瘤做好准备 有利于免疫激活的微环境。我们的中心假设不仅是我们的ImFusion针头设计 将提高信息技术。药物传递，但高温介导的肿瘤血管变化也将 消除免疫屏障，增强I.T.免疫治疗的疗效。因此，总体目标是 这项建议的目的是了解1)注射技术和热剂量的变化对I.T.药物 2)热疗影响肿瘤血管和免疫微环境，3)热疗 补充I.T.同基因大鼠肝细胞癌模型的免疫治疗。我们将在以下方面验证我们的假设 具体目标：1)明确注射技术和热疗对I.T.的影响。交付；2)确定 作为热剂量和时间函数的热疗对肿瘤微环境的影响；3) 描述热疗与I.T.结合时的局部和远期影响。免疫疗法。这个 建议是创新的，因为它追求多模式图像引导的方法，以最大限度地提高肿瘤免疫力。 在这样做的时候，作为局部治疗的体温过高的范例被 体温过高是一种“免疫引爆剂”。这项拟议的研究意义重大，因为它预计将有一个 对晚期肝癌患者免疫治疗疗效的广泛翻译影响。

ABSTRACT Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths in the US. Immunotherapy is a promising new treatment approach for HCC, but there are numerous barriers to immunotherapy in HCC. Local intratumoral injection of immunotherapies is a logical solution to overcoming these barriers, particularly given the fact that local immune activation can drive systemic tumor immunity. However, there are substantial gaps in knowledge regarding the intratumoral delivery of immunotherapies. When delivered through conventional needles, injected medications track along the needle path and leak out into the surrounding normal tissue. Not only does this minimize treatment efficacy due to diminished on-target delivery, but it also increases systemic toxicities. Moreover, even with local deposition of immunotherapies, persistent microenvironmental barriers can inhibit the generation of tumor immunity. This application will evaluate a novel intratumoral drug delivery system with an adjustable, electrically insulating sleeve specifically designed for intratumoral delivery of immunotherapies (ImFusion system). In addition to the controlled delivery of injected drugs, ImFusion also allows for radiofrequency-mediated intratumoral hyperthermia generation. Preliminary data show that the ImFusion system results in a substantial improvement in intratumoral drug delivery relative to conventional needles, and that its hyperthermia capabilities can “prime” the tumor microenvironment for immune activation. Our central hypothesis is not only that our ImFusion needle design will improve i.t. drug delivery, but also that the hyperthermia-mediated alterations to tumor vascularity will countervail immunologic barriers and augment i.t. immunotherapy efficacy. Accordingly, the overall objectives of this proposal are to understand how 1) variations in injection technique and thermal dose influence i.t. drug deposition, 2) hyperthermia affects tumor vascularity and immune microenvironments, and 3) hyperthermia complements i.t. immunotherapy in a syngeneic rat model of HCC. We will test our hypothesis in the following specific aims: 1) Define the influence of injection technique and hyperthermia on i.t. delivery; 2) Determine the tumor microenvironmental ramifications of hyperthermia as a function of thermal dose and time; and 3) Characterize the local and abscopal effects of hyperthermia when combined with i.t. immunotherapy. The proposal is innovative because it pursues a multimodality image-guided approach to maximize tumor immunity. In doing so, the paradigm of hyperthermia as a locoregional therapy is replaced with the paradigm of hyperthermia as an “immune primer.” The proposed research is significant because it is expected to have a broad translational impact on the efficacy of immunotherapy for patients with advanced HCC.