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

使用 TCR 测序改变 CTCL 患者的诊断和护理

• 批准号: 9460470
• 负责人: Rachael Ann Clark
• 金额: $ 67.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-23 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9460470
• 关键词: Benign; Biotechnology; Blood; Caring; Cells; Clinic; Clinical; Clinical Trials; Clinical assessments; Clone Cells; Collaborations; Collection; Country; Cutaneous Lymphoma; Cutaneous T-cell lymphoma; Data; Diagnosis; Diagnostic tests; Disease; Early Diagnosis; Evaluation; Goals; High-Throughput Nucleotide Sequencing; Hospitals; Immune; Individual; Industrialization; Inflammation; Inflammatory; Lead; Literature; Malignant - descriptor; Malignant Neoplasms; Measures; Methodology; Methods; Monitor; Non-Hodgkin' s Lymphoma; Patient Care; Patients; Physicians; Prognostic Marker; Reproducibility; Research; Resources; Sampling; Scientist; Services; Skin; Specimen; Symptoms; T-Cell Receptor; T-Lymphocyte; T-cell diversity; Techniques; Technology; Testing; Time; Translational Research; Treatment Efficacy; Woman; base; clinical care; design; experimental study; high risk; improved; industry partner; innovation; lymph nodes; medical schools; multidisciplinary; next generation; novel; novel therapeutics; outcome forecast; prognostic assays; public health relevance; research clinical testing; response; skin disorder; skin lesion; tool; translational physician; treatment response; tumor progression

 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.

 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 的诊断很困难，平均需要六年时间，常常会延迟诊断，直到疾病变得更具侵袭性。其次，20% 的早期患者会发展为进行性的、通常致命的疾病，并且没有有效的方法来识别 将会进步的患者。第三，CTCL既是皮肤淋巴瘤又是炎症性疾病。皮肤炎症的临床评估并不一定反映恶性 T 细胞负担，这使得确定治疗反应变得困难。我们提供的试点数据表明，高通量 TCR CDR3 测序 (HTS) 可以通过识别和量化皮肤病变中的恶性克隆 T 细胞来诊断 CTCL，即使是在早期阶段。我们表明，它首次允许对皮肤病变中的恶性和良性 T 细胞浸润进行全面研究，这可能会产生识别将出现进展的患者的方法。最后，该技术能够量化恶性 T 细胞，这使得它作为评估治疗反应的一种方式远远优于临床检查。 HTS 可用作研究和临床测试，但目前尚未在 CTCL 诊所中使用，因为其在 CTCL 中的实用性和可靠性尚未得到证实。我们组建了一支由工业科学家、CTCL 转化研究医师科学家专家和 CTCL 患者护理医师专家组成的多机构、多学科协作团队。我们的工业合作伙伴 Adaptive Biotechnologies 是高温超导技术的先驱。我们的学术合作伙伴哈佛医学院布莱根妇女医院是世界公认的 CTCL 转化研究中心。我们与全国三个顶级 CTCL 临床护理中心建立了合作，以识别和提供患者样本。在目标 1 中，我们提出了旨在证明对恶性克隆的评估与前 5 个良性克隆的百分比相结合的实验，即使在早期阶段也能明确诊断 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，我们将在三个独立的临床试验中利用 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方式，并将 HTS 广泛用作 CTCL 诊所的诊断和预后测试。