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。 美国，5年总生存率仅为22%。尽管癌症免疫疗法能够产生 BrCa在多种癌症类型中具有持久的反应，但BrCa的免疫排斥反应罕见且自发 退化异常。因此，对于联合组合疗法范例存在强有力的先例， 通过增强肿瘤免疫原性和/或抑制免疫抑制性来增强免疫疗法（ITx） 机制等在这项提案中，我们将系统地评估聚焦超声（FUS）的能力-a 用于非侵入性、非电离声能沉积到肿瘤中技术-以增强适应性免疫 针对BrCa转移，并与选定的免疫疗法协同作用。UVA是FUS ITx的全球领导者 研究，两项"首次在人体"的临床试验正在进行中，以评估FUS与PD1阻断剂的组合 在实体瘤（包括转移性BrCa）和第三项试验中评估FUS和吉西他滨， 用于免疫介导的BrCa肿瘤控制。这些试验都伴随着一个同伴成像试验 旨在通过PET/CT评估患者肿瘤沉积物中的CD8 + T细胞浸润，该方法还将 纳入我们的临床前研究。为此，该提案利用这些临床试验以及 强大的临床前计划，以加强植根于免疫学领域的高度转化研究管道， 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，可提供转移性BrCa治疗的量子改善潜力。这是 实现三个具体目标。在具体目标1中，我们将扩展有趣的早期临床和临床前 研究结果确定FUS方案，当与骨髓靶向治疗联合使用时， 针对原发性和播散性BrCa肿瘤（例如脑肿瘤）的嵌合抗原受体（CAR）T细胞疗法 转移）。在具体目标2中，我们将设计基于FUS的治疗诊断技术，用于BrCa的液体活检， 为了（i）发现对FUS和ITx反应的新生物标志物（ii）在低浓度的环境中进行液体活检， 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） 通过FUS和ITx推进BrCa精准护理。这一建议的高度创新目标有助于系统地 推进FUS在CAR T细胞治疗、癌症生物标志物发现和个性化治疗中的作用的方法 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.