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

摘要 肝细胞癌（HCC）是美国癌症相关死亡增长最快的原因。 免疫治疗是一种有前途的肝癌新治疗方法，但免疫治疗存在许多障碍。 免疫治疗HCC局部瘤内注射免疫疗法是克服肿瘤复发的合理解决方案。 这些障碍，特别是考虑到局部免疫激活可以驱动全身肿瘤免疫的事实。 然而，关于免疫疗法的肿瘤内递送的知识存在很大差距。 当通过常规针输送时，注射的药物沿着针路径沿着行进并泄漏 进入周围的正常组织这不仅由于减少了靶向治疗而使治疗效果最小化， 但它也增加了全身毒性。此外，即使局部沉积免疫疗法， 持久的微环境屏障可抑制肿瘤免疫的产生。此应用程序将 评估一种新型的肿瘤内药物输送系统，具有可调节的电绝缘套管， 设计用于免疫疗法的肿瘤内递送（ImFusion系统）。除了控制下交付 在注射药物的情况下，ImFusion还允许射频介导的肿瘤内热疗产生。 初步数据显示，ImFusion系统显著改善了肿瘤内药物治疗。 相对于传统的针头，它的热疗能力可以“引发”肿瘤 免疫激活的微环境。我们的中心假设不仅是我们的ImFusion针设计 将改善i.t.药物输送，而且高血压介导的肿瘤血管分布的改变将 抵消免疫屏障并增强i.t.免疫治疗效果。因此，总体目标 1）注射技术和热剂量的变化如何影响i.t.药物 沉积，2）高温影响肿瘤血管和免疫微环境，3）高温 补体i.t.免疫疗法在HCC的同基因大鼠模型中的应用。我们将在下面测试我们的假设 具体目的：1）确定注射技术和热疗对i.t.（2）确定 作为热剂量和时间的函数的热疗的肿瘤微环境分支;以及3） 描述高温与i.t.结合时的局部和远位效应。免疫疗法的 该提案是创新的，因为它追求多模态图像引导方法以最大化肿瘤免疫。 在这样做时，热疗作为局部区域治疗的范例被以下范例取代： 热疗作为“免疫引物”拟议的研究是重要的，因为它预计将有一个 对晚期HCC患者免疫治疗的疗效具有广泛的转化影响。

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.