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

摘要 乳腺癌肿瘤学的一个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、提高存活率的药物取而代之。近年 在肿瘤来源的外来体中看到指数兴趣;纳米尺寸（30-150 nm）囊泡大量脱落 由肿瘤细胞产生，并载有来自其母体肿瘤细胞的致癌货物。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、对治疗的抗性、组织侵袭和转移。乳腺癌 外泌体在其表面表达癌蛋白，这些癌蛋白已被证明在干扰细胞增殖中发挥直接作用。 治疗性单克隆抗体的活性和对抗化疗剂。这几行 证据有力地支持发展限制肿瘤来源的外来体的作用的策略，然而， 不存在这样的靶向治疗策略。拟议的研究需要对一种医疗器械进行体外评价， 设备，血液净化器，作为从乳腺癌患者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体外血液透析盒，其包含： 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感染性病毒的可行性研究，这些病毒具有相似的大小和 糖基化特征作为癌症外泌体。Aethlon还获得了快速访问途径（EAP） FDA的指定，以支持血液净化器治疗危及生命的病毒的进步。为 该器械使用的前瞻性新适应症，我们的中心假设是血液净化器可用于 通过从血浆中捕获和去除这些囊泡来靶向乳腺癌外泌体。在本研究中， 源自三阴性和HER 2过表达乳腺癌细胞的外来体将用作模型 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 增长所提出的概念验证研究将提供对外泌体是否被靶向的深入了解。 血液净化器具有与疾病相关的特征和功能。我们设想体外 从循环中去除疾病介导的外泌体的方法可以取代或减少对毒性药物的需求。 药物或揭露其功效，可以想象作为标准护理乳腺癌治疗的辅助手段。

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.