Automation of MicroC3 as a CDx for myeloma therapies

多发性骨髓瘤（MM）是一种使人衰弱且目前无法治愈的血液恶性肿瘤。而中位数 生存期增加到5 - 7年，MM患者最终复发并对治疗产生耐药性。一旦 他们到达这个阶段，这往往是一个试验和错误的过程，直到可以找到一个有效的治疗。此外， MM骨髓肿瘤微环境在疾病进展和抗肿瘤药物治疗中起重要作用。 疗法迫切需要一种临床工具，能够预测对特定药物的治疗反应。 患者我们开发了一种离体微流控平台MicroC 3 ™，可以快速分析治疗药物， 患者的MM细胞对与其自身微环境细胞共培养的各种药物的反应 件.当最初通过测量患者MM细胞的离体毒性反应来测试MicroC 3时， 对于MM治疗中常用的药物硼替佐米，MicroC 3反应可分为两组 回顾性地正确识别所有患者的临床反应或无反应， 含硼替佐米的疗法。我们建议开发和自动化MicroC 3作为一种伴随诊断， 硼替佐米和其他MM疗法。为了实现这一项目，Lynx Biosciences通过以下方式获得了独特的定位： 四个关键合作：1）娜塔莉卡兰德博士作为合作者和威斯康星州大学主任 骨髓瘤临床项目，2）大卫毕比教授作为一个专家顾问和先驱的简单的微流体 设备，3）Salus Discovery，作为开发自动化样品处理工作流程的合作者，以及4） Microfluidic ChipShop是一家拥有多年开发和制造经验的制造合作伙伴， 微型医疗设备平台。该提案包括两个目标：1）制定GMP流程， 注塑成型MicroC 3设备的制造，2）在内部自动化细胞分离、接种和处理 MicroC3.在第一阶段结束时，我们将开发出大部分的临床框架， 技术的推广。我们将有一个可靠和强大的过程，为制造和操作的 MicroC 3准备好处理第二阶段所需的更大规模。第二阶段将包括一项前瞻性临床试验， 通过使用自动化检测平台来隔离患者进行治疗，测试MicroC 3的预测能力 含有硼替佐米和潜在的其他疗法。最终，MicroC 3可以应用于恢复 在后期临床试验中不成功的药物，确定潜在的成功的临床前药物 临床试验开始前，以及MM以外的血液学恶性肿瘤。

Multiple myeloma (MM) is a debilitating and currently incurable hematological malignancy. While the median survival has increased to 5 – 7 years, MM patients ultimately relapse and become resistant to therapy. Once they reach this stage, it is often a trial and error process until an effective therapy can be found. Furthermore, the MM bone marrow tumor microenvironment plays a significant role in disease progression and resistance to therapy. There is a critical need for a clinical tool able to predict therapeutic response to drugs for specific patients. We have developed an ex vivo microfluidic platform, MicroC3™, that can rapidly analyze the therapeutic response of a patient’s MM cells to various drugs in coculture with their own microenvironmental cell components. When MicroC3 was initially tested by measuring the ex vivo toxicity responses of patient MM cells to bortezomib, a drug commonly used in MM therapy, MicroC3 responses could be segregated into two groups which retrospectively correctly identified all patients as either clinically responsive or non-responsive to bortezomib-containing therapies. We propose to develop and automate MicroC3 as a companion diagnostic for bortezomib, and other MM therapies. To achieve this project, Lynx Biosciences is uniquely positioned through four key collaborations: 1) Dr. Natalie Callander as a collaborator and Director of the University of Wisconsin Myeloma Clinical Program, 2) Professor David Beebe as an expert consultant and pioneer of simple microfluidic devices, 3) Salus Discovery, as a collaborator to develop an automated sample processing workflow, and 4) Microfluidic ChipShop, a manufacturing partner with years of experience in development and fabrication of microscale medical device platforms. The proposal consists of two aims: 1) To develop a GMP process for fabrication of injection molded MicroC3 devices, 2) To automate cell isolation, seeding, and treatment within MicroC3. At the conclusion of Phase I, we will have developed a large portion of the framework for the clinical rollout of the technology. We will have a reliable and robust process for both the fabrication and operation of the MicroC3 ready to handle the larger scale required for Phase II. Phase II will include a prospective clinical trial to test the predictive capabilities of MicroC3 by using the automated assay platform to segregate patients for therapy containing bortezomib and potentially other therapies. Ultimately, MicroC3 may be applied for use in reviving drugs which were not successful in late stage clinical trials, identifying potentially successful preclinical drugs prior to initiation of clinical trials, and hematological malignancies other than MM.