Automation of MicroC3 as a CDx for myeloma therapies

多发性骨髓瘤(MM)是一种衰弱的、目前无法治愈的血液系统恶性肿瘤。而中位数 生存期增加到5-7年，多发性骨髓瘤患者最终复发并对治疗产生抵抗。一次 他们达到这个阶段，这通常是一个反复试验的过程，直到找到有效的治疗方法。此外， 多发性骨髓瘤微环境在疾病进展和抗药性中起重要作用 心理治疗。迫切需要一种能够预测特定药物治疗反应的临床工具。 病人。我们开发了一种体外微流控平台MicroC3™，可以快速分析治疗药物 患者MM细胞与自身微环境细胞共培养时对多种药物的反应 组件。当最初通过测量患者MM细胞的体外毒性反应来测试MicroC3时 对于MM治疗中常用的药物Bortezomib，MicroC3反应可以分为两组 追溯正确地将所有患者识别为临床有反应或无反应 含有硼替佐米的疗法。我们建议开发MicroC3并使其自动化，作为对 波特佐米和其他MM疗法。为了实现这个项目，Lynx生物科学公司通过以下方式进行了独特的定位 四项关键合作：1)娜塔莉·卡兰德博士作为威斯康星大学的合作者和主任 骨髓瘤临床计划，2)大卫·毕比教授是简单微流控技术的专家顾问和先驱 设备，3)Salus Discovery，作为协作者开发自动化样品处理工作流程，以及4) 微流控芯片车间，拥有多年开发和制造经验的制造合作伙伴 微型医疗器械平台。该提案包括两个目标：1)为以下目标制定GMP流程 制造注塑MicroC3器件，2)实现细胞分离、播种和处理的自动化 MicroC3。在第一阶段结束时，我们将开发出临床框架的很大一部分 这项技术的推出。我们将拥有可靠和坚固的工艺，用于制造和运行 MicroC3准备处理第二阶段所需的更大规模。第二阶段将包括一项预期的临床试验，以 通过使用自动分析平台隔离患者进行治疗，测试MicroC3的预测能力 含有波特佐米和可能的其他疗法。最终，MicroC3可能被应用于复苏 在晚期临床试验中不成功的药物，确定可能成功的临床前药物 在开始临床试验之前，以及MM以外的血液系统恶性肿瘤。

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.