Cutaneous T-cell lymphoma (CTCL) is a clonally-derived, skin-invasive malignancy of CD4+ T-lymphocytes with the phenotype of mature helper T-cells. Patients with advanced forms of CTCL characterized by multiple tumors or peripheral blood involvement typically have a poor prognosis. Our previous work has demonstrated that advanced CTCL is characterized by prominent immunologic defects including depressed cell-mediated immunity. A marked defect in IL-12 production in CTCL has also been noted, which may play a role in depressed cell-mediated immunity. Because evidence exists for an antitumor T-cell response and since IL-12 is pivotal in stimulating cytotoxic T-cells, our IL-12 multicenter trial group has completed a small phase I dose escalation trial of IL-12 with 5 of 9 evaluable patients responding and a phase II single dose trial with 10 of 23 evaluable patients responding. Key observations in these small studies were 1)responses were rapid but were often eventually associated with an IL-12 refractory state associated with the plateau of the clinical response 2) the latter may possibly be associated with down modulation of IL-12 receptors on lymphocytes 3) regressing lesions were intensely infiltrated with cytotoxic T-cells and 4) more robust responses occurred at the lower dose of 100 ng/kg used in the phase I trial. This project will utilize viably cryopreserved peripheral blood lymphoid cells as well as biopsy specimens obtained from participating patients in the previous phase I and II IL-12 trials. We propose to investigate the in vivo mechanisms of action of IL-12 by studying 1) skin infiltrating immune cells, 2) cytokine production in situ in skin lesions, and 3) extent of apoptosis within active skin lesions prior to and during IL-12 therapy and correlate this with lesion regression during the past trials. We will also examine IL-12 responsive NK cell activity and interferon gamma production in concert with IL-12 receptor expression and IL-12 signal transduction on lymphoid cells obtained from patients prior to and during therapy to determine if down modulation of receptors or alteration of Jak-Stat pathways accounts for tolerance (refractoriness) to the clinical effects of IL-12. The results of these studies will further improve our understanding of the mechanisms of action of IL-12 and will assist in targeting a more effective dose of IL-12 for CTCL. Moreover, in a new clinical study to be funded under a separate project, the addition of low-dose IL-2 to IL-12 may yield a more efficacious combination of agents which may synergistically enhance anti-tumor immunity and clinical responses. Skin and blood specimens to be obtained in this new phase II study will also be examined in the above assays.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA093372-01
Application #
6543600
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2001-09-28
Project End
2003-09-27
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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