The Hemopurifier Device for Targeted Removal of Breast Cancer Exosomes from the Blood Circulation

用于从血液循环中靶向去除乳腺癌外泌体的血液净化器装置

• 批准号: 9620493
• 负责人: Annette Marleau
• 金额: $ 29.84万
• 依托单位: AETHLON MEDICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9620493
• 关键词: Achievement; Address; Affinity; Agglutinins; Blood; Blood Circulation; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; CSPG4 gene; Cancer Patient; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Development; Device Designs; Devices; Disease; ERBB2 gene; Evaluation; Excision; FDA approved; Feasibility Studies; Flow Cytometry; Galanthus nivalis; Goals; Hematopoietic Neoplasms; Hemodialysis; Hemofiltration; Hour; Human; Immune; Immunophenotyping; Immunosuppression; Individual; Laboratories; Lectin; Life; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical Device; Methods; Modeling; Molecular Sieve Chromatography; Natural Killer Cells; Neoplasm Metastasis; Non-Malignant; Oncogenic; Oncoproteins; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Plasmapheresis; Population; Protocols documentation; Research; Research Support; Role; SLEB2 gene; Stromal Cells; Stromal Neoplasm; Surface; Survival Rate; T-Lymphocyte; TNFSF10 gene; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Tissues; Treatment Protocols; Tumor-Derived; Universities; Ursidae Family; Validation; Vesicle; Virus; base; chemotherapeutic agent; design; exosome; experimental study; glycosylation; immune function; improved; insight; interest; magnetic beads; malignant breast neoplasm; nanosized; nanovesicle; neoplastic cell; oncology; overexpression; prospective; research study; standard of care; success; targeted treatment; therapy resistant; tumor; tumor growth

ABSTRACT An overarching challenge in breast cancer oncology is the urgency to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and improve the rates of survival. Recent years have seen exponential interest in tumor-derived exosomes; nano-sized (30-150 nm) vesicles shed in large quantities by tumor cells and laden with oncogenic cargo from their parent tumor cell. Research studies have shown that breast cancer cells produce copious quantities of exosomes that are released systemically and mediate tumor- associated immune suppression, resistance to therapies, tissue invasion, and metastasis. Breast cancer exosomes express oncoproteins on their surfaces that have been shown to exert direct actions in interfering with the activity of therapeutic monoclonal antibodies, and countering chemotherapeutic agents. These lines of evidence strongly support the development of strategies to limit the effects of tumor-derived exosomes, however, no such targeted therapeutic strategy exists. The proposed research entails an ex vivo evaluation of a medical device, the Hemopurifier, as a strategy for the capture and removal of exosomes from the plasma of breast cancer patients. The clinical-grade Hemopurifier comprises an extracorporeal hemodialysis cartridge containing a lectin (Galanthus nivalis agglutinin; GNA) affinity matrix. Aethlon has successfully completed an FDA-approved feasibility study using the Hemopurifier for addressing infectious viruses, which have similar sizes and glycosylation signatures as cancer exosomes. Aethlon has also received an Expedited Access Pathway (EAP) designation from the FDA to support the advancement of the Hemopurifier to treat life-threatening viruses. For this prospective new indication for use of the device, our central hypothesis is that the Hemopurifier can be used to target breast cancer exosomes by capturing and removing these vesicles from plasma. In this study, exosomes originating from triple negative and HER2-overexpressing breast cancer cells will be used as a model since research studies have defined the functions of these vesicles in immunosuppression and promoting tumor growth. The proposed proof of concept studies will provide insight into whether exosomes targeted by the Hemopurifier possess signatures and functions that are disease-relevant. We envision that an extracorporeal approach for removing disease-mediating exosomes from circulation may replace or reduce the need for toxic drugs or unmask their efficacy, conceivably serving as an adjunct to standard of care breast cancer treatments.

摘要 乳腺癌肿瘤学面临的最大挑战是迫切需要通过以下方式改革治疗方案 取而代之的是更有效、毒性更低、存活率更高的药物。近年来， 对肿瘤来源的外切体表现出指数级的兴趣；纳米尺寸(30-150 nm)的囊泡大量脱落 由肿瘤细胞携带并携带来自其亲代肿瘤细胞的致癌货物。研究表明， 乳腺癌细胞产生大量的外体，这些外体被系统地释放，并介导肿瘤- 相关的免疫抑制、对治疗的抵抗、组织侵袭和转移。乳腺癌 外切体在其表面表达癌蛋白，已被证明在干扰 治疗性单抗的活性，以及抗化疗药物。这些产品线 然而，有证据有力地支持制定策略来限制肿瘤来源的外切体的影响， 不存在这种有针对性的治疗策略。这项拟议的研究需要对一名医生进行体外评估 血液净化器，作为捕获和去除乳房血浆中外切体的一种策略 癌症患者。该临床级血液透析器包括体外血液透析盒，该透析盒包含 凝集素(雪花莲凝集素；GNA)亲和基质。艾斯隆公司已经成功完成了FDA批准的 使用血液净化器处理传染性病毒的可行性研究，这些病毒具有相似的大小和 糖基化标记为癌症外切体。Aethlon还获得了快速通道(EAP) FDA指定支持血液净化器的进步，以治疗危及生命的病毒。为 这是该设备使用的新适应症，我们的中心假设是血液净化器可以使用 通过从血浆中捕获和移除这些小泡来靶向乳腺癌外切体。在这项研究中， 来自三重阴性和HER2过表达的乳腺癌细胞的外切体将被用作模型 由于研究已经确定了这些囊泡在免疫抑制和促进肿瘤中的功能 成长。拟议的概念验证研究将提供洞察，了解外显体是否被 血液净化器具有与疾病相关的特征和功能。我们设想一种体外循环 从循环中去除介导性疾病的外切体的方法可以取代或减少对有毒物质的需求 药物或揭示其疗效，可想而知，作为乳腺癌治疗标准的辅助护理。