Development of Molecular Microbubble Probes and Ultrasound-Guidance in Immunotherapeutic Strategies

项目摘要/摘要 尽管免疫疗法在治疗癌症方面取得了前所未有的效果，但超过50%-80%的患者不会 对治疗有反应，并将忍受由于治疗而产生的严重不良反应和危及生命的事件。方法 选择或指导免疫治疗策略是当务之急。我们建议开发基于超声波的 表征被忽视的组织免疫成像属性的方法；血管系统和相关 内皮细胞。在癌症中，肿瘤血管和相关的内皮细胞高度异常， 免疫抑制。根据患者的不同，这些也有很大的不同。调整的方法 血管和内皮免疫已经发展起来，其中抗血管生成剂被用来直接 针对这些，提高免疫治疗的效果。然而，抗血管生成药物的时机和剂量与 免疫治疗仍然是最大限度地使所有患者受益的主要挑战。因此，我们提出的工具 发展将有助于1)选择最有可能对免疫疗法有反应的患者，并减少不良反应 对无反应者的效果和成本，以及2)为指导联合抗血管生成提供成像反馈 和免疫治疗方案，使更多的患者可以受益于无与伦比的效果 这些治疗。为了实现我们的目标，我们将：1)开发独特的分子超声探头 成像内皮细胞免疫抑制表面标志物，以及2)开发图像引导以优化 探索定量超声参数空间的免疫治疗策略。配备了这些设备 最初的发展，我们的目标将是启动一个更大的研究计划，旨在进一步开发 定量超声方法成像免疫系统的组织、血管和内皮方面。

PROJECT SUMMARY/ABSTRACT Despite the unprecedented effects of immunotherapy in treating cancer, over 50–80% of patients will not respond to treatment and will endure severe adverse and life-threatening events due to treatment. Approaches to select or guide immunotherapeutic strategies are urgently needed. We propose to develop ultrasound-based approaches to characterize an overlooked attribute of tissue immuno-imaging; the vasculature and associated endothelium. In cancer, tumor blood vessels and associated endothelial cells are highly abnormal and immunosuppressive. These also differ extensively on a patient-by-patient basis. Approaches to modulate vascular and endothelial immunity have been developed, where anti-angiogenic agents are used to directly target these and enhance the effects of immunotherapy. However, timing and dosing of anti-angiogenics with immunotherapy remains a major challenge to maximize benefits to all patients. As such, the tools we propose to develop will help 1) select patients that are most likely to respond to immunotherapy and reduce adverse effects and costs to non-responders, and 2) provide imaging feedback for guiding combined anti-angiogenic and immunotherapy treatment regimens so that more patients may benefit from the unparalleled effects of these treatments. In order to achieve our goals, we will: 1) develop unique molecular ultrasound probes for imaging endothelial cell immunosuppressive surface markers, and 2) develop image-guidance to optimize immunotherapeutic strategies by exploring the quantitative ultrasound parameter space. Equipped with these initial developments, our goal will be to initiate a larger research program designed to further develop quantitative ultrasound approaches for imaging tissue, vascular and endothelial aspects of the immune system.