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

项目总结/摘要 尽管免疫疗法在治疗癌症方面具有前所未有的效果，但超过50-80%的患者不会接受免疫疗法。 对治疗有反应，并将忍受治疗引起的严重不良和危及生命的事件。方法 选择或指导免疫策略是迫切需要的。我们建议开发基于超声波的 表征组织免疫成像的被忽视的属性的方法;脉管系统和相关的 内皮细胞在癌症中，肿瘤血管和相关的内皮细胞高度异常， 免疫抑制这些也因患者而异。调节方法 已经开发了血管和内皮免疫，其中抗血管生成剂用于直接 靶向这些并增强免疫治疗的效果。然而，抗血管生成药物的时机和剂量与 免疫治疗仍然是使所有患者获益最大化的主要挑战。因此，我们提出的工具 开发将有助于1）选择最有可能对免疫疗法产生反应的患者，并减少不良反应 无反应者的效果和成本，以及2）提供成像反馈，用于指导联合抗血管生成 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，和2）开发图像引导，以优化 通过探索定量超声参数空间来确定免疫策略。配备这些 初步发展，我们的目标将是启动一个更大的研究计划，旨在进一步发展 定量超声方法用于免疫系统的组织、血管和内皮成像。

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.