Microarray Analysis of Responsiveness of CTCL IL-12

CTCL IL-12 反应性的微阵列分析

• 批准号: 7027059
• 负责人: LOUISE C. SHOWE
• 金额: $ 31.18万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027059
• 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(申请人提供)：CTCL是一种知之甚少的癌症，对常规治疗如化疗无效。使用生物反应调节剂(如IFNA)治疗较为成功，但许多患者仍然具有抵抗力，反应背后的机制尚不清楚。此外，最初对治疗有反应的患者经常随着时间的推移而对治疗产生抵抗力。在CTCL的所有阶段都可以观察到IL-12产生的严重缺陷，但在CTCL的晚期最为严重。最近的一项I期临床试验表明，IL-12治疗CTCL可以诱导CTCL患者的皮损消退和细胞毒性T细胞反应。我们之前对45例Sezary综合征(SS)患者的全球基因表达研究进行了分析，发现了新的诊断标记物和定义了一类预后特别差的患者的标记物，即使他们的肿瘤负担可能很低。我们现在希望扩展这些研究，以确定CTCL患者对IL-12治疗的反应性的基因表达谱。在NIH资助的一项为期3年的多中心II期临床试验中，将对46名CTCL患者的样本进行分析，以评估IL-12治疗CTCL患者的疗效。将在13周的IL-12治疗期间收集样本，并通过微阵列分析，以确定与以下因素相关的基因表达“特征”：1)对治疗的反应性；2)缺乏反应性；3)IL-12抵抗力的发展；以及4)治疗过程中疾病的发展。在研究的第二阶段，IL-2将与IL-12一起被引入，以确定IL-2是否能够增强单独使用IL-12没有完全反应的患者、对IL-12治疗无效的患者或发展为进展性疾病的患者的更有效的临床反应。接受IL-122治疗的患者的样本也将通过微阵列进行分析，以确定与治疗反应或无反应相关的基因表达特征模式。在疾病进展的情况下，识别那些治疗无效或有害的患者的基因“签名”将导致更知情的IL-12治疗方案。识别与治疗反应相关的特征将有助于更好地了解CTCL的生物学特性。