GENE EXPRESSION IN CTCL PATIENTS IN IL 12 CLINICAL TRIAL

描述：（申请人的摘要）皮肤T细胞淋巴瘤（CTCL）， 包括蕈样肉芽肿（MF）和塞扎里综合征（SS）是惰性的 淋巴瘤的进展阶段，开始与皮肤病变，进行 通过白血病阶段与循环肿瘤细胞，并最终扩散 到内脏器官。目前还没有治愈CTCL的方法， 对一个病人有效对另一个病人无效 似乎是一个非常相似的疾病水平。CTCL细胞已经被认为是 与辅助性T细胞2型（Th 2）T细胞相关，基于检测到的 Th 2细胞因子（例如，IL-4和IL-5）和先天免疫应答降低 患者展示。申请人对细胞因子受体的初步研究 CTCL中的基因表达（IL-12 R和IFN-γ R）支持 在7名SS患者中，有6名患者的SS细胞转化为Th 2细胞，但这也表明， 患者在这方面可能会有所不同，这取决于 检查CTCL。SS患者PBL体外治疗的观察 与IL-12联合使用可以：1）诱导Th 1细胞因子水平（例如，IFN-γ和IL-2） 与正常对照产生的水平相似，2）激活CD 8 + 细胞毒性，提示与CTCL相关的免疫异常 可以通过IL-12治疗有利地改变。为了支持这一假设， 在有限的I期毒性试验中，IL-12治疗CTCL患者显示， 对IL-12的反应率为50%，目前正在进行多中心II期试验。 中求进工作总本申请提出系统地分析多基因 表达模式，使用cDNA微阵列，在IL-12患者的样品中， 在IL-12治疗之前、期间和之后进行的II期试验。最初的重点 这些研究中的一部分将针对已经报道的CTCL中失调的基因， 例如p53，其表达或不表达的基因的特征在于 正常Th 2细胞，如IL-12 R β 2基因和IFN-γ R β链 基因，以及其表达与细胞介导的免疫相关的基因 反应患者中的基因表达模式将与IL-12相关 通过比较基线模式的差异， 确定可能与发育相关的基因表达变化 快速抗药性或抗药性。特征识别 区分响应性和非响应性， 临床医生避免使患者接受无效治疗， 找出那些反应良好的病人的理解 导致快速耐受的遗传事件可以提供线索， 可能重新诱导IL-12反应性的临时疗法。

DESCRIPTION: (Applicant's Abstract) The cutaneous T-cell lymphomas (CTCL) which including Mycosis fungoides (MF) and Sezary syndrome (SS) are indolent lymphomas that progress in stages, starting with skin lesions, proceeding through a leukemic phase with circulating tumor cells and eventually spreading to the visceral organs. There is presently no cure for CTCL and a therapy that is effective for one patient may be ineffective for another patient with what appears to be a very similar level of disease. CTCL cells have been suggested to be related to T helper type 2 (Th2) T-cells based on detected expression of Th2 cytokines (e.g., IL-4 and IL-5) and a depressed innate immune response exhibited by patients. The applicant's preliminary studies of cytokine receptor gene expression (IL-12R and IFN-gamma R) in CTCL supports the relationship of SS cells to Th2 cells in six of seven SS patients, but also suggests that patients may vary from one another in this respect depending on the stage of CTCL examined. Observations that treatment of PBL from SS patients in vitro with IL-12 could; 1) induce levels of Th1 cytokines (e.g., IFN-gamma and IL-2) to levels similar to that produced by normal controls and, 2) activate CD8+ cytotoxicity, suggested that the immune abnormalities associated with CTCL could be favorably altered by IL-12 therapy. In support of this hypothesis, IL-12 treatment of CTCL patients in limited, Phase I toxicity trials showed a 50% response rate to IL-12 and a multi-center Phase II trial is now in progress. This application proposes to systematically analyze multi-gene expression patterns, using cDNA microarrays, in samples from patients in IL-12 Phase II trials taken before, during and after IL-12 therapy. The initial focus of these studies will be on genes already reported to be disregulated in CTCL such as p53, genes whose expression or lack of expression is characteristic of normal Th2 cells such as the IL-12R beta 2 gene and the IFN-gamma R beta chain gene, and genes whose expression is associated with a cell mediated immune response. Gene expression patterns among patients will be correlated with IL-12 responsiveness by comparing differences in baseline patterns and attempt to identify changes in gene expression that may be associated with the development of tachyphylaxis or resistance to treatment. Identification of characteristics that differentiate between responsiveness and non-responsiveness would allow clinicians to avoid subjecting patients to ineffective therapies and to identify patients that would be good responders. An understanding of the genetic events that lead to tachyphylaxis could provide clues to alternate interim therapies that might reinduce IL-12 responsiveness.