Immunoengineering Next-Generation Cancer Therapies with Focused Ultrasound

聚焦超声免疫工程下一代癌症疗法

• 批准号: 10693947
• 负责人: Natasha Diba Sheybani
• 金额: $ 39.6万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693947
• 关键词: Abbreviations; Acceleration; Acoustics; Adjuvant; Administrator; Ally; Appointment; Authorship; Biomedical Engineering; Biopsy Specimen; Blood Screening; Breast Cancer Patient; Breast Cancer therapy; Breast cancer metastasis; CAR T cell therapy; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Prognosis; Cessation of life; Clinical; Clinical Protocols; Clinical Trials; Collaborations; Combination immunotherapy; Companions; Data; Deposition; Disease; Drug Delivery Systems; Engineering; Extramural Activities; Fellowship; Focused Ultrasound; Foundations; Funding; Genomics; Goals; HRK gene; Home; Human Resources; Image; Imaging Techniques; Immune; ImmunoPET; Immunologics; Immunology; Immunooncology; Immunotherapy; Infrastructure; Institution; Institutional Review Boards; International; Intervention; Knowledge; Lesion; Maps; Mechanics; Mediating; Mentors; Mentorship; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Molecular; Monitor; Multimodal Imaging; Mus; Myelogenous; Outcome; PD-1 blockade; PET/CT scan; Patients; Peer Review; Peripheral; Play; Positioning Attribute; Postdoctoral Fellow; Precision therapeutics; Publications; Radiogenomics; Radiology Specialty; Recurrence; Regimen; Research; Research Training; Resources; Role; Solid Neoplasm; Structure; T cell infiltration; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Time; Training; Translating; Translational Research; Treatment Efficacy; Tumor Immunity; Tumor Markers; Tumor Tissue; United States; United States National Institutes of Health; Universities; University of Virginia Cancer Center; Virginia; Woman; adaptive immune response; adaptive immunity; advanced breast cancer; anti-PD-1; anti-tumor immune response; biomarker discovery; biomedical imaging; cancer biomarkers; cancer genomics; cancer immunotherapy; cancer therapy; cancer type; career; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; circulating biomarkers; combinatorial; design; exosome; first-in-human; forging; fortification; gemcitabine; genomic data; genomic signature; graduate student; imaging informatics; immunoengineering; immunogenicity; improved; innovation; liquid biopsy; machine learning framework; malignant breast neoplasm; member; molecular imaging; mortality; next generation; novel; novel marker; personalized immunotherapy; personalized medicine; pre-clinical; precision oncology; preclinical study; predict clinical outcome; predicting response; prognostic; programs; quantum; radiological imaging; radiomics; research faculty; response; response biomarker; risk stratification; senior faculty; skills; synergism; targeted treatment; tenure track; theranostics; tool; translational pipeline; trial design; tumor; tumor DNA; ultrasound

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.

项目摘要 转移性乳腺癌（BRCA）是统一妇女癌症死亡率的第二个最普遍的原因 州，总体生存率仅为22％。尽管癌症免疫疗法能够产生 多种癌症类型的持久反应，BRCA的免疫原理排斥很少见，并且赞助商 回归不寻常。那是盟军组合疗法范式有一个很强的先例 通过增强肿瘤免疫原性和/或抑制免疫抑制，增强免疫疗法（ITX） 机制。在此提案中，我们将系统地评估集中超声（FUS）的能力 - a 非侵入性，非电离声能沉积到肿瘤中的技术 - 增强适应性免疫组织化学 反对BRCA转移并与选定的免疫疗法协同作用。 UVA是FUS ITX的世界领导者 研究，正在进行两项“人类第一”临床试验，以评估FUS与PD1封锁的组合 在实体瘤（包括转移性BRCA）和第三次试验待定批准中，以评估FUS和吉西他滨 用于免疫介导的BRCA肿瘤的控制。这些试验伴随着同伴成像试验 设计用于评估患者肿瘤沉积物中CD8+ T细胞的浸润，这种方法也将 被整合到我们的临床前研究中。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翻译的研究管道， 分子成像，液体活检和放射基因组学。使用此工具包，我们打算设计和实施 FUS+ITX组合为转移性BRCA疗法的量子改善提供了潜力。这是 在三个特定目标中实现。在特定的目标1中，我们将扩大有趣的早期临床和临床前和临床前 发现识别FUS方案的结果，当与粒细胞靶向疗法结合使用时，会增强的有效性 嵌合抗原受体（CAR）T细胞疗法针对原发性和散布的BRCA肿瘤（例如脑 转移）。在特定的目标2中，我们将在BRCA中设计基于FUS的液体活检的疗法技术 为了（i）发现对FUS和ITX的反应的新型生物标志物（II）在较低的情况下进行液体活检 循环肿瘤生物标志物的基本水平。最后，在特定的目标3中，我们将构建机器学习 将放射学数据与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） 用FUS和ITX推进BRCA精确护理。该提案的高度创新目标借给系统的 促进FU在CAR T细胞疗法，癌症生物标志物发现和个性化中的作用的方法 ITX，因此有望改善转移性乳腺癌患者的生活。