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.

抽象的 乳腺癌肿瘤学的首要挑战是迫切需要通过以下方式彻底改变治疗方案： 用更有效、毒性更小的药物替代它们，并提高生存率。近年来有 人们对肿瘤来源的外泌体的兴趣呈指数级增长；纳米尺寸（30-150 nm）的囊泡大量脱落 由肿瘤细胞产生，并充满来自其亲本肿瘤细胞的致癌物质。研究表明 乳腺癌细胞产生大量的外泌体，这些外泌体被全身释放并介导肿瘤 相关的免疫抑制、治疗抵抗、组织侵袭和转移。乳腺癌 外泌体在其表面表达癌蛋白，这些蛋白已被证明可以发挥直接干扰作用 治疗性单克隆抗体和对抗化疗药物的活性。这些行 证据强烈支持制定限制肿瘤来源的外泌体影响的策略，然而， 不存在这样的靶向治疗策略。拟议的研究需要对医学进行离体评估 设备，血液净化器，作为从乳腺血浆中捕获和去除外泌体的策略 癌症患者。临床级血液净化器包括一个体外血液透析盒，其中含有 凝集素（雪花莲凝集素；GNA）亲和基质。 Aethlon 已成功完成 FDA 批准的 使用血液净化器处理具有相似大小和形状的传染性病毒的可行性研究 作为癌症外泌体的糖基化特征。 Aethlon 还获得了快速访问途径 (EAP) FDA 指定支持血液净化器的进步，以治疗危及生命的病毒。为了 对于使用该设备的这一前瞻性新适应症，我们的中心假设是可以使用血液净化器 通过从血浆中捕获和去除这些囊泡来靶向乳腺癌外泌体。在这项研究中， 来自三阴性和 HER2 过表达乳腺癌细胞的外泌体将被用作模型 因为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 生长。拟议的概念验证研究将深入了解外泌体是否被靶向 血液净化器具有与疾病相关的特征和功能。我们设想一个体外 从循环中去除介导疾病的外泌体的方法可能会取代或减少对有毒物质的需求 药物或揭示其功效，可以想象作为乳腺癌护理标准治疗的辅助手段。