Transforming the diagnosis and care of patients with CTCL using TCR sequencing

 描述（由申请人提供）：在治疗皮肤T细胞淋巴瘤（CTCL）、以炎性皮肤病变为特征的非霍奇金淋巴瘤中存在三个主要临床问题。首先，早期CTCL的诊断是困难的，平均需要六年的时间，通常会延迟诊断，直到疾病变得更具侵略性。第二，20%的早期患者会发展成进行性的、往往是致命的疾病，而且目前还没有有效的方法来识别 患者会进步。第三，CTCL既是一种皮肤淋巴瘤，也是一种炎症性疾病。皮肤炎症的临床评估并不一定反映恶性T细胞负荷，使得难以确定对治疗的反应。我们提供的试验数据表明，高通量TCR CDR3测序（HTS）可以通过识别和定量皮肤病变中的恶性克隆T细胞来诊断CTCL，即使在其最早阶段。我们表明，它允许第一次全面研究的恶性和良性T细胞浸润的皮肤病变，可能导致的方法，用于确定患者谁将进步。最后，这种技术量化恶性T细胞的能力使其大大上级临床检查作为评估治疗反应的一种方式。HTS可作为研究和临床试验，但目前尚未用于CTCL诊所，因为其在CTCL中的实用性和可靠性尚未得到证实。我们组建了一个多机构，多学科的合作团队，由工业科学家，CTCL转化研究的医生科学家专家和CTCL患者护理的医生专家组成。我们的工业合作伙伴Adaptive Biotechnologies是HTS技术的先驱。我们的学术合作伙伴，哈佛医学院布里格姆妇女医院，是世界公认的CTCL转化研究中心。我们与全国三家顶级CTCL临床护理中心建立了合作关系，以识别和提供患者样本。在目标1中，我们提出了旨在证明恶性克隆的评价，结合前五名良性克隆的百分比，即使在其最早阶段也能明确诊断CTCL，并将其与良性炎症性皮肤病区分开来。在目标2中，我们将评估预测其他癌症进展的基于免疫的参数，以确定它们是否可以识别将发展为进展性CTCL的患者。在目标3中，我们将在三项独立的临床试验中使用HTS，以明确证明其在评估治疗反应方面优于临床检查。该提案的目标是证明HTS可以彻底改变CTCL的诊断和监测方式，改变这些患者的护理，并将HTS作为CTCL诊所的诊断和预后测试。

 DESCRIPTION (provided by applicant): There are three major clinical problems in treating cutaneous T-cell lymphomas (CTCL), non- Hodgkin's lymphomas characterized by inflammatory skin lesions. First, diagnosis of early-stage CTCL is difficult and takes on average six years, often delaying diagnosis until the disease becomes more aggressive. Second, 20% of early stage patients go on to progressive, often lethal disease and there is no validated way to identify patients who will progress. Third, CTCL is both a skin lymphoma and inflammatory disease. Clinical assessment of skin inflammation doesn't necessarily reflect malignant T cell burden, making determination of responses to therapy difficult. We provide pilot data that high throughput TCR CDR3 sequencing (HTS) can diagnose CTCL even in its earliest stages by identifying and quantifying malignant clonal T cells in skin lesions. We show that it permits for the first time comprehensive studies of the malignant and benign T cell infiltrate in skin lesions that may lead to methods for identifying patients who will progress. Lastly, the ability of this technique to quantify malignant T cells makes it vastly superior to clinical examination as a way to assess responses to therapy. HTS is available as both a research and clinical test but is not currently used in CTCL clinics because its utility and reliability in CTCL have not been demonstrated. We have assembled a multi-institutional, multidisciplinary collaborative team of industrial scientists, physician scientist's expert in CTCL translational research and physician's expert in the care of CTCL patients. Our Industrial Partner, Adaptive Biotechnologies, is a pioneer in HTS technology. Our Academic Partner, Brigham and Women's Hospital at Harvard Medical School, is a world recognized center for CTCL translational research. We have forged a collaboration with three of the top CTCL Clinical Care Centers in the nation to identify and supply patient samples. In Aim 1, we propose experiments designed to demonstrate that evaluation of the malignant clone, combined with percentages of the top five benign clones, definitively diagnoses CTCL even in its earliest stages and discriminates it from benign inflammatory skin diseases. In Aim 2, we will evaluate immune based parameters predictive of progression in other cancers to determine if they can identify patients who will develop progressive CTCL. In Aim 3, we will utilize HTS in three separate clinical trials to definitively demonstrate its superiority to clinical examination in assessing responses to therapy. The goal of this proposal is to demonstrate that HTS can revolutionize the way CTCL is diagnosed and monitored, transforming the care of these patients and bringing HTS into common use as a diagnostic and prognostic test in CTCL clinics.