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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CBSS (01))
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Wu, Roy S
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Wistar Institute
United States
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Rook, Alain H; Benoit, Bernice; Kim, Ellen J et al. (2010) Immune modulators as therapeutic agents for cutaneous T-cell lymphoma. Clin Lymphoma Myeloma Leuk 10 Suppl 2:S93-5
Nebozhyn, Michael; Loboda, Andrey; Kari, Laszlo et al. (2006) Quantitative PCR on 5 genes reliably identifies CTCL patients with 5% to 99% circulating tumor cells with 90% accuracy. Blood 107:3189-96