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

一种图像引导免疫治疗和热疗装置，用于克服晚期肝细胞癌的肿瘤免疫障碍

• 批准号: 10585715
• 负责人: Rahul Anil Sheth
• 金额: $ 46.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585715
• 关键词: Abscopal effect; Address; Affect; Agonist; Blood Vessels; Cancer Etiology; Cessation of life; Clinical; Clinical Trials; Complement; Data; Deposition; Devices; Dose; Drug Delivery Systems; Engineering; Foundations; Generations; Goals; Hour; Hyperthermia; Immune; Immune response; Immunologics; Immunotherapy; Injections; Knowledge; Mediating; Mission; Multimodal Imaging; Needles; Neoplasm Metastasis; Normal tissue morphology; Patients; Perfusion; Pharmaceutical Preparations; Primary Neoplasm; Primary carcinoma of the liver cells; Public Health; Rattus; Research; Research Support; Site; Stimulator of Interferon Genes; System; Systemic Therapy; T cell infiltration; Techniques; Technology; Testing; Time; Treatment Efficacy; Tumor Immunity; Variant; cancer therapy; clinical translation; combat; cytotoxic CD8 T cells; design; drug distribution; image guided; image guided intervention; immune activation; immunostimulatory therapy; improved; innovation; interstitial; liver cancer model; minimally invasive; mortality; novel; novel therapeutic intervention; preclinical study; pressure; radio frequency; success; systemic toxicity; targeted delivery; time interval; tool; translational impact; treatment strategy; trend; tumor; tumor hypoxia; tumor microenvironment; tumor-immune system interactions

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.

抽象的 肝细胞癌（HCC）是美国与癌症相关死亡的增长最快的原因。 免疫疗法是HCC的一种有希望的新方法，但是有许多障碍 HCC的免疫疗法。局部肿瘤内免疫疗法是克服的逻辑解决方案 这些障碍，特别是考虑到局部免疫激活可以驱动全身性肿瘤免疫的事实。 但是，关于免疫疗法的肿瘤内递送存在很大的差距。 当通过常规针交付时，沿着针路的注射药物轨道并泄漏 进入周围的正常组织。这不仅可以最大程度地减少因目标降低而导致的治疗效率 交付，但也增加了系统性毒性。此外，即使在当地沉积免疫疗法， 持续的微环境屏障可以抑制肿瘤免疫学的产生。此应用程序将 用可调节的，电绝缘套管专门评估一种新型的肿瘤内药物输送系统 专为免疫疗法（Infusion System）的肿瘤内输送而设计。除了受控交付 在注射药物中，融合还允许射频介导的肿瘤内高温产生。 初步数据表明，灌注系统会大大改善肿瘤内药物 相对于常规针的交付 微环境免疫激活。我们的中心假设不仅是我们的Imfusion针头设计 将改善I.T.药物输送，但热疗介导的肿瘤血管的改变将 反击免疫障碍和增强I.T.免疫疗法有效性。因此，总体目标 该建议的内容是了解1）注射技术和热剂量影响的变化I.T.药品 沉积，2）高温影响肿瘤血管和免疫环境，3） 赔偿I.T. HCC的合成大鼠模型中的免疫疗法。我们将在下面检验我们的假设 具体目的：1）定义注射技术和高温对I.T.的影响。送货; 2）确定 肿瘤微疗的肿瘤微环境分析与热剂量和时间的关系； 3） 当与I.T.免疫疗法。这 提案具有创新性，因为它采用多模式图像引导的方法来最大化肿瘤免疫史。 这样，用作为局部疗法的高温范式取代了 热疗作为“免疫底漆”。拟议的研究很重要，因为预计它将具有 对晚期HCC患者的免疫疗法效率的翻译广泛影响。