GENE EXPRESSION IN CTCL PATIENTS IN IL 12 CLINICAL TRIAL

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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.