GENE EXPRESSION IN CTCL PATIENTS IN IL 12 CLINICAL TRIAL

描述：(申请人摘要)皮肤T细胞淋巴瘤 包括真菌病(MF)和Sezary综合征(SS)都是惰性的 分期发展的淋巴瘤，从皮肤损害开始，进展 通过白血病阶段与循环中的肿瘤细胞并最终扩散 内脏器官。目前，CTCL还没有治愈方法，而且有一种疗法可以 对一名患者有效，对另一名患者无效 似乎是一种非常相似的疾病水平。CTCL细胞已经被认为是 根据检测到的表达与T辅助2型(Th2)T细胞相关 Th2细胞因子(如IL-4和IL-5)与抑制的先天免疫反应 病人表现出来的。申请人对细胞因子受体的初步研究 CTCL的基因表达(IL-12R和干扰素-γR)支持 7例SS患者中有6例SS细胞向Th2细胞转化，但也提示 患者在这方面可能会有所不同，这取决于患者的阶段 CTCL检查。SS患者外周血淋巴细胞的体外治疗观察 IL-12可：1)诱导Th1细胞因子水平(如干扰素-γ和IL-2) 达到与正常对照组相似的水平，2)激活CD8+ 细胞毒性，提示与CTCL相关的免疫异常 可通过IL-12治疗而有利地改变。为了支持这一假设， IL-12治疗CTCL患者的有限、I期毒性试验显示 对IL-12的应答率为50%，多中心II期试验目前正在进行中 进步。这项应用提出了对多基因进行系统分析 用基因芯片技术研究IL-12患者样本的表达模式 在IL-12治疗前、治疗中和治疗后进行II期试验。最初的焦点 这些研究的重点将是已报道的CTCL失控基因 例如P53，其表达或缺失表达的基因是 正常Th2细胞，如IL-12Rβ2基因和干扰素-γRβ链 基因，以及其表达与细胞免疫相关的基因 回应。患者的基因表达模式将与IL-12相关 通过比较基线模式的差异来实现响应能力，并尝试 确定可能与发育相关的基因表达变化 或对治疗产生抵抗力。特征的识别 有反应和无反应的区别将允许 临床医生避免让病人接受无效的治疗和 找出那些能做出良好反应的病人。对这一概念的理解 导致快速呼吸暂停的遗传事件可能会提供线索 可能重新诱导IL-12应答的过渡疗法。

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.