Evaluation of an implantable microdevice for rapid cancer drug screening directly in T cell lymphoma patients

项目概要/摘要： 晚期皮肤T细胞淋巴瘤（CTCL）和外周T细胞淋巴瘤（PTCL）的生存率非常低 由于有限的有效治疗。三个主要障碍阻碍了药物开发：1） 每种T细胞淋巴瘤（TCL）亚型的患者，这限制了样本的可用性和临床试验的招募; 2)亚型间的遗传和组织微环境变异性;以及3）缺乏细胞和动物模型 来测试免疫疗法因此，在开发TCL的新治疗方法方面存在重大的科学差距。 在这里，我们建议使用一种创新的植入式微型设备（MD），比一粒米还小， 直接放入患者的癌性病变中，以筛选药物并确定最有效的癌症药物 在个性化水平上治疗TCL。我们的MD将多达20种任何类别的药物输送到非重叠区域 一个肿瘤。它是通过一个小针进入皮肤，并在3天内取出切除装置沿沿着 用标准的皮肤活检工具切除几毫米的癌组织。该设备允许测试 因此，我们可以将药物以微剂量直接注射到活体肿瘤内，从而避免了全身副作用的风险。药物 灵敏度由装置周围肿瘤的组织学评估确定。md和 一种用于处理和分析组织的方法已经在小鼠模型中的多种癌症类型中得到验证 目前正在进行一项针对乳腺癌的试点研究。这些研究的具体目标是： i）确定在TCL的皮肤病变中植入和取回MD的安全性和可行性; TCL对通过MD递送的癌症治疗的反应性，通过使用 高度多重循环免疫荧光，一种能够表征亚细胞变化的新平台 在药物治疗后的天然免疫微环境中，用超过30种标记物，和iii） TCL的遗传异常与药物反应，以确定潜在的生物标志物的反应，并确定 如果MD可用于通过将局部组织对药物的反应与 患者对相同药物全身给药时的临床反应。我们假设原位组织 药物在TCL中的分布可以预测对标准治疗的全身反应， 作为多种研究性单一或联合治疗的快速筛查。此外，基因组和 肿瘤的免疫表型分析可以帮助鉴定治疗的预测性生物标志物。的 我们的研究结果将把临床试验的努力集中在最有前途的治疗策略上， TCL的精准医疗时代。

Project Summary/Abstract: Advanced cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL) have very poor survival due to limited effective treatments. Three major obstacles have stalled drug development: 1) the low number of patients with each T-cell lymphoma (TCL) subtype, which limits sample availability and clinical trial enrollment; 2) genetic and tissue microenvironment variability across subtypes; and 3) a lack of cellular and animal models to test immunotherapies. Thus, there is a major scientific gap in the development of new treatments for TCL. Here, we propose the use of an innovative implantable microdevice (MD), smaller than a grain of rice, that is placed directly into a patient's cancerous lesion to screen drugs and to identify the most effective cancer drug to treat TCL on a personalized level. Our MD delivers up to 20 drugs of any class into non-overlapping regions of a tumor. It is delivered into the skin with a small needle and retrieved in 3 days by excising the device along with a few millimeters of surrounding cancer tissue with a standard skin biopsy tool. This device allows testing drugs directly inside the living tumor with microdoses, thereby avoiding the risk of systemic side effects. Drug sensitivity is determined by histologic assessment of the tumor surrounding the device. The MD and the method for processing and analyzing tissue has been validated across multiple cancer types in mouse models and is being evaluated in an ongoing pilot study in breast cancer. The specific aims of these studies will be to: i) determine the safety and feasibility of implanting and retrieving the MD in skin lesions of TCL; ii) assess local responsiveness of TCL to cancer treatments delivered via the MD through microscopic assessments using highly multiplexed cyclic immunofluorescence, a novel platform capable of characterizing subcellular changes in the native immune microenvironment following drug treatment with over 30 markers, and iii) correlate genetic abnormalities of TCL with drug response to identify potential biomarkers of response and to determine if the MD can be used to predict clinical response by correlating the local tissue response to drug with a patient's clinical response to the same drug when given systemically. We hypothesize that in situ tissue profiling of drugs in TCL can predict systemic responses to standard of care therapies and therefore can serve as a rapid screen for multiple investigational single or combination treatments. Additionally, genomic and immunophenotypic analysis of tumors may assist in identification of predictive biomarkers of treatment. The results of our studies will focus clinical trial efforts toward the most promising treatment strategies and usher in the era of precision medicine in TCL.