Immunoengineering Next-Generation Cancer Therapies with Focused Ultrasound

项目摘要 转移性乳腺癌(BRCA)是美国女性癌症死亡的第二大常见原因 5年的总体存活率仅为22%。尽管癌症免疫疗法能够产生 对各种癌症类型的持久反应，BRCA的免疫排斥反应是罕见的和自发的 回归不寻常。因此，联合组合治疗范例有很强的先例 通过提高肿瘤的免疫原性和/或抑制免疫抑制来加强免疫治疗(ITX 机械装置。在这项提案中，我们将系统地评估聚焦超声(FUS)的能力。 非侵入性、非电离声能沉积到肿瘤中的技术--增强适应性免疫 抗BRCA转移，并与选定的免疫疗法协同作用。UVA是FUS ITX的世界领先者 目前正在进行两项“人类首例”临床试验，以评估FUS与PD1阻滞剂的组合 实体肿瘤(包括转移性BRCA)和第三项试验正在等待批准，以评估FUS和吉西他滨 用于免疫介导性控制BRCA肿瘤。这些试验伴随着一个伴随的成像试验。 旨在通过PET/CT评估患者肿瘤沉积中CD8+T细胞的渗透，这一方法也将 整合到我们的临床前研究中。为此，该提案利用了这些临床试验以及 强大的临床前计划，以加强植根于免疫学领域的高度翻译的研究渠道， 分子成像、液体活检和放射基因组学。有了这个工具包，我们打算设计和实现 FUS+ITX组合，为转移性BRCA治疗提供量子改进的潜力。这是 实现了三个具体目标。在具体目标1中，我们将扩大引人入胜的早期临床和临床前 确定FUS方案的发现，当与髓系靶向治疗相结合时，增强 嵌合抗原受体(CAR)T细胞治疗原发和播散性BRCA肿瘤(如脑 转移)。在具体目标2中，我们将设计基于FUS的射频消融技术用于BRCA的液体活组织检查 目的：(I)发现对FUS和ITX有反应的新生物标志物；(Ii)使液体活组织检查能够在低血压环境中进行 循环肿瘤生物标志物的基础水平。最后，在具体目标3中，我们将构建机器学习 将放射学数据与来自液体活检标本的基因组数据相结合的框架(例如放射基因组学) 以FUS和ITX推进BRCA精准护理。这项提案的高度创新的目标有助于系统地 提高FUS在CAR T细胞治疗、肿瘤生物标记物发现和个性化中作用的途径 ITX，从而有望改善转移性乳腺癌患者的生活。

Project Abstract Metastatic breast cancer (BrCa) is the 2nd most prevalent cause of cancer mortality in women in the United States, with a 5-year overall survival of only 22%. Though cancer immunotherapies are capable of generating durable responses across a variety of cancer types, immunologic rejection of BrCa is rare and spontaneous regression unusual. Thus, there exists a strong precedent for allied combinatorial therapy paradigms that potentiate immunotherapy (ITx) by boosting tumor immunogenicity and/or curbing immunosuppressive mechanisms. In this proposal, we will systematically assess the capacity of focused ultrasound (FUS) - a technique for non-invasive, non-ionizing acoustic energy deposition into tumors – to potentiate adaptive immunity against BrCa metastases and synergize with selected immunotherapies. UVA is a world leader in FUS ITx research, with two “first-in-human” clinical trials underway to evaluate combinations of FUS with PD1 blockade in solid tumors (including metastatic BrCa) and a third trial pending approval to evaluate FUS and gemcitabine for immune-mediated control of BrCa tumors. These trials are accompanied by a companion imaging trial designed to evaluate CD8+ T cell infiltration in patients’ tumor deposits via PET/CT, an approach that will also be integrated into our pre-clinical studies. To this end, this proposal leverages these clinical trials as well as a robust pre-clinical program to fortify a highly translational research pipeline rooted in the domains of immunology, molecular imaging, liquid biopsy and radiogenomics. With this toolkit, we intend to design and implement FUS+ITx combinations that offer the potential for quantum improvements in metastatic BrCa therapy. This is achieved in three Specific Aims. In Specific Aim 1, we will expand on intriguing early clinical and pre-clinical findings to identify FUS regimens that, when combined with myeloid-targeted therapies, augment the efficacy of chimeric antigen receptor (CAR) T cell therapy against primary and disseminated BrCa tumors (e.g. brain metastases). In Specific Aim 2, we will engineer FUS-based theranostic technologies for liquid biopsy in BrCa in order to (i) discover novel biomarkers of response to FUS and ITx (ii) enable liquid biopsy in settings with low basal levels of circulating tumor biomarkers. Finally, in Specific Aim 3, we will construct machine learning frameworks that integrate radiological data with genomic data from liquid biopsy specimens (e.g. radiogenomics) to advance BrCa precision care with FUS and ITx. The highly innovate aims of this proposal lend to a systematic approach for advancing the role of FUS in CAR T cell therapy, cancer biomarker discovery and personalized ITx, thereby promising to improve the lives of metastatic breast cancer patients.