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

项目摘要/摘要： 晚期皮肤T细胞淋巴瘤(CTCL)和外周T细胞淋巴瘤(PTCL)存活率很低 由于有效的治疗方法有限。三大障碍阻碍了药物开发：1)药物数量较少 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登记； 2)不同亚型间的遗传和组织微环境变异性；3)缺乏细胞和动物模型 来测试免疫疗法。因此，在TCL的新治疗方法的开发方面存在着重大的科学差距。 在这里，我们建议使用一种创新的植入式微设备(MD)，它比一粒米还小，也就是 直接放入患者的癌症病变中以筛选药物并确定最有效的抗癌药物 在个性化的层面上对待TCL。我们的MD最多可将任何类别的20种药物输送到非重叠区域 肿瘤的症状。用一根小针将它送入皮肤，并在3天内切除设备将其取出 用标准的皮肤活检工具在周围几毫米长的癌症组织上进行检查。此设备可用于测试 药物直接在活体肿瘤内使用微量，从而避免了全身副作用的风险。药效 敏感度由装置周围肿瘤的组织学评估决定。医学博士和 在小鼠模型中，处理和分析组织的方法已经在多种癌症类型中得到验证 并正在进行的乳腺癌试点研究中进行评估。这些研究的具体目标是： I)确定在TCL皮损中植入和取回MD的安全性和可行性；ii)评估局部 通过显微镜评估TCL对MD提供的癌症治疗的反应性 高度多元化的循环免疫荧光--一种能够表征亚细胞变化的新平台 在药物治疗后的自然免疫微环境中，有超过30个标志物，并且iii)相关 TCL基因异常与药物反应识别潜在的生物反应标志物 如果MD可以通过将局部组织对药物的反应与 患者全身给药时对同一药物的临床反应。我们假设原位组织 TCL中的药物概况可以预测对标准护理治疗的全身反应，因此可以 作为多个研究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能有助于识别治疗的预测生物标志物。这个 我们的研究结果将把临床试验的努力集中在最有希望的治疗策略上，并迎来 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.