Microarray Analysis of Responsiveness of CTCL IL-12

描述（由申请人提供）：CTCL是一种鲜为人知的癌症，对化疗等常规治疗无反应。使用IFNa等生物反应调节剂治疗更为成功，但许多患者仍然具有耐药性，而且反应性背后的机制尚不清楚。此外，最初对治疗有反应的患者往往随着时间的推移而对治疗产生耐药性。在CTCL的所有阶段都观察到IL-12产生的严重缺陷，但在晚期CTCL中最为严重。最近的一项I期临床试验表明，IL-12治疗可诱导CTCL患者病变消退和细胞毒性t细胞反应。我们之前对45例Sezary综合征（即白血病型CTCL）患者样本的全球基因表达研究进行了分析，发现了新的诊断标志物和一类预后特别差的患者的标志物，尽管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，将分析46例CTCL患者的样本，以评估IL-12治疗CTCL患者的疗效。样本将在为期13周的IL-12处理期间收集，并通过微阵列分析以确定与；1)对治疗的反应性；2)缺乏反应性；3)IL-12耐药性的发展；4)治疗期间疾病的进展。在该研究的第二阶段，IL-2将与IL-12一起引入，以确定IL-2是否可以增强单独使用IL-12没有完全缓解的患者，对IL-12治疗变得难治性或发展为进行性疾病的患者的更有效的临床反应。接受IL-122治疗的患者样本也将通过微阵列进行分析，以确定与治疗反应性或无反应性相关的基因表达特征模式。在疾病进展的情况下，识别出那些治疗无效或有害的患者的基因“特征”，将导致更明智的IL-12治疗方案。识别与治疗反应性相关的特征将有助于更好地了解CTCL的生物学。

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.