Microarray Analysis of Responsiveness of CTCL IL-12

CTCL IL-12 反应性的微阵列分析

• 批准号: 6760654
• 负责人: LOUISE C. SHOWE
• 金额: $ 31.17万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760654
• 关键词: biotechnology; clinical research; drug resistance; flow cytometry; gene expression; genetic markers; human subject; human therapy evaluation; immunocytochemistry; interleukin 12; interleukin 2; microarray technology; mycosis fungoides lymphoma; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; patient oriented research; polymerase chain reaction

DESCRIPTION (provided by applicant): CTCL is a poorly understood cancer which is unresponsive to conventional treatments such as chemotherapy. Treatments with biological response modifiers such as IFNa have been more successful but many patients remain resistant and the mechanisms behind responsiveness are not well understood. In addition patients that respond to therapy initially frequently develop resistance to treatment with time. A profound defect in IL-12 production is observed in CTCL at all stages, but most profoundly in advanced stages of CTCL. A recent Phase I clinical trial has shown that IL-12 therapy of CTCL can induce lesion regression and cytotoxic T-cell responses in CTCL patients. Our previous analysis of global gene expression studies of 45 samples from patients with Sezary Syndrome (SS) the leukemic version of CTCL identified new markers for diagnosis and markers that define a class of patients with particularly poor prognosis even though their tumor burden may be low. We now want to extend those studies to identify gene expression profiles that characterize responsiveness to IL-12 therapy in patients with CTCL. Samples will be analyzed from 46 CTCL patients, in an NIH funded, 3 year multi center Phase II clinical trial to assess the efficacy of IL-12 treatment for patients with CTCL. Samples will be collected over a 13 week period of IL-12 treatment and analyzed by microarrays to identify gene expression "signatures" that correlate with; 1) responsiveness to therapy 2) lack of responsiveness 3) the development of IL-12 resistance, and 4) the development of progressive disease during therapy. In a second phase of the study IL-2 will be introduced in conjunction with IL-12 to determine whether IL-2 can potentiate a more effective clinical response in patients that do not exhibit a complete response with IL-12 alone, that become refractory to IL-12 treatment or that develop progressive disease. Samples from patients treated with IL-122 will also be analyzed by microarrays to identify characteristic patterns of gene expression that correlate with responsiveness or non-responsiveness to the therapy. Identification of gene "signatures" that identify those patients for whom treatment will be ineffective or deleterious, in the case of progressive disease, will lead to more informed protocols for treatment with IL-12. Identification of characteristics that correlate with responsiveness to therapy will provide a better understanding of the biology of CTCL.

描述（由申请人提供）：CTCL是一种对常规治疗（如化疗）无反应的知之甚少的癌症。使用生物反应调节剂（如IFNa）的治疗更为成功，但许多患者仍然具有耐药性，并且反应性背后的机制尚未得到很好的理解。此外，最初对治疗有反应的患者随着时间的推移经常对治疗产生耐药性。在CTCL的所有阶段都观察到IL-12产生的严重缺陷，但在CTCL的晚期阶段最严重。最近的I期临床试验表明，CTCL的IL-12治疗可以在CTCL患者中诱导病变消退和细胞毒性T细胞应答。我们之前对45例Sezary综合征（SS）患者（CTCL的白血病版本）的全球基因表达研究进行了分析，确定了新的诊断标志物和定义一类预后特别差的患者的标志物，即使他们的肿瘤负荷可能很低。我们现在希望扩展这些研究，以确定CTCL患者对IL-12治疗反应性的基因表达谱。将在NIH资助的3年多中心II期临床试验中分析来自46名CTCL患者的样品，以评估IL-12治疗CTCL患者的功效。将在IL-12治疗的13周期间收集样品，并通过微阵列分析以鉴定与以下相关的基因表达“特征”：1）对治疗的响应性2）缺乏响应性3）IL-12抗性的发展，和4）治疗期间进行性疾病的发展。在研究的第二阶段，将IL-2与IL-12联合引入，以确定IL-2是否可以在单独使用IL-12未表现出完全应答、对IL-12治疗变得难治或发展为进行性疾病的患者中增强更有效的临床应答。还将通过微阵列分析来自用IL-122治疗的患者的样品，以鉴定与对治疗的反应性或非反应性相关的基因表达的特征模式。在进行性疾病的情况下，鉴定那些治疗无效或有害的患者的基因“签名”的鉴定将导致更明智的IL-12治疗方案。识别与对治疗的反应性相关的特征将提供对CTCL生物学的更好理解。