Interventional method development for multiplexed personalized drug evaluation using implantable microdevices

摘要：新型可植入微型装置(IMD)可直接植入患者肿瘤内，可快速评估 原位多药反应。它们可用于任何实体肿瘤，以提供直接、全面、空间多方面的 20种药物的基因组读数同时显示，有可能使液体和组织活检生物标志物黯然失色 能力。然而，在肿瘤中放置和检索IMD目前需要高度侵入性的手术 患者发病率和并发症风险过高。对于大多数癌症患者来说，这些风险令人望而却步， 因此，正在进行的首例人类IMD试验的登记人数有限。 我们已经开发出一种完全介入(微创)的非手术方法来放置和取回 IMDS。我们使用定制的穿刺针活检设备和图像引导，仅提供并精确移除IMD 以及邻近的毒品暴露组织。这是一个简单的门诊手术，类似于常规的经皮肿瘤。 活组织检查，使用单一的微小(2毫米)皮肤切口。它降低了使用IMD的发病率和风险，并将 大幅增加目前和未来临床IMD试验的登记人数。然而，一项对动物进行的临床前研究 需要模型来证明这种介入方法在技术上的可行性和安全性。 为人类所用。 这项建议描述了一项在兔后肢肿瘤模型中进行的临床前研究，该模型接近于模拟 典型的软组织肉瘤环境，有以下具体目的：1)确定我们的技术可行性 介入(非手术)途径用于IMD的放置和取出；以及2)确定总体安全性和 相同干预方法的不良事件发生率。介入性IMD放置和检索程序 将在一个由15只兔子组成的统计队列中进行。技术可行性和安全终点将是 评估并用于为进一步的方法改进和最终的第一次人体试验提供信息。 这项拟议的研究具有创新性，因为它将开发和验证个性化的新干预工具 可以作为下一代肿瘤活检的癌症治疗。它意义重大，因为它将直接使 一项评估晚期软组织肉瘤患者基于IMD的药物优化的首例人体试验。它 还将使更多的人参加其他类似或风险较低的解剖区域正在进行的IMD临床试验 (例如乳房)。最终，如果临床验证基于IMD的个性化治疗的总体长期目标 实现了最优化，所开发的介入方法可以适用于任何肿瘤学 有经皮可及肿瘤的患者(类似于常规经皮组织活检)。

Abstract: Novel implantable miniaturized devices (IMDs) placed directly in patient tumors can rapidly evaluate multi-drug responses in-situ. They can be used in any solid tumor to provide direct, comprehensive, spatial multi- omic readouts of >20 drugs simultaneously, with potential to eclipse liquid and tissue biopsy biomarker capabilities. However, placing and retrieving IMDs in tumors currently requires highly invasive surgery with excessively high patient morbidity and complication risks. For most cancer patients, these risks are prohibitive, and as a result ongoing first-in-human IMD trials have had limited enrollment. We have developed a fully interventional (minimally invasive) non-surgical method to place and retrieve IMDs. We use custom needle biopsy devices and image guidance to deliver and precisely remove only the IMD and adjacent drug-exposed tissue. This is a simple outpatient procedure similar to routine percutaneous tumor biopsies, using a single tiny (<2mm) skin incision. It reduces the morbidity and risks of IMD use, and would greatly increase enrollment in current and future clinical IMD trials. However, a preclinical study in an animal model is needed to demonstrate technical feasibility and safety of this interventional method prior to first-in- human use. This proposal describes a preclinical study in a rabbit hindlimb tumor model that closely simulates a typical soft tissue sarcoma setting, with the following specific aims: 1) determine the technical feasibility of our interventional (non-surgical) approach for IMD-placement and retrieval; and 2) determine the overall safety and adverse event rate of this same interventional method. Interventional IMD placement and retrieval procedures will be performed in a statistically-powered cohort of 15 rabbits. Technical feasibility and safety endpoints will be assessed, and used to inform further method refinement and ultimately first-in-human trials. The proposed study is innovative as it will develop and validate new interventional tools for personalized cancer treatment that could serve as the next generation of tumor biopsy. It is significant as it will directly enable a first-in-human trial to evaluate IMD-based drug optimization in patients with advanced soft tissue sarcomas. It will also enable greater enrollment in ongoing IMD clinical trials in other similar or lower risk anatomic regions (e.g. breast). Ultimately, if the overall long-term goal of clinically validating IMD-based personalized treatment optimization is achieved, the interventional methods developed here could be applicable to every oncology patient with a percutaneously accessible tumor (similar to routine percutaneous tissue biopsies).