Cutaneous T-cell lymphoma (CTCL) is a clonally-derived, skin-invasive malignancy of CD4+ T-lymphocytes with the phenotype of mature helper T-cells. Our previous work has demonstrated that the Sezary form, or typically leukemic form of CTCL, is characterized by prominent immunologic defects including depressed cell-mediated immunity. We have also demonstrated increased production of T-helper type 2 (Th2) cytokines (IL-4, IL-5) and deficient production of Th1 cytokines (IL-2 and interferon gamma [IFN gamma]) by their peripheral blood cells (PBMC) as well as detecting IL-4 and IL-5 mRNA within lesional skin but not normal skin of patients with all stages of CTCL. A marked defect in IL-12 production in CTCL has also been noted, which may also 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, we have completed a phase I trial of IL-12 conducted in our GCRC to treat CTCL. Our data indicate that IL-12 has marked therapeutic activity. This K24 translational grant should permit the P.I. greater time to focus on understanding the in vivo mechanisms of action of IL-12 and other therapeutically active cytokines by studying 1) skin immune cells, 2) cytokine expression, and 3) extent of apoptosis within active skin lesions prior to and during IL-12 therapy and correlate this with lesion regression. We will also characterize the effects of IL- 12 to inhibit growth and induce apoptosis of the purified malignant CD4+ T-cells and determine if there is in vitro synergism with the therapeutically active agent, IFN alpha. We will also examine IL-12 receptor expression prior to and prospectively during therapy to determine if downmodulation of receptors accounts for tolerance to the clinical effects of IL-12. Since our preliminary data indicate that IFN alpha upregulates IL-12 receptor expression on the peripheral blood cells of CTCL patients, we will determine if interferons in vitro can enhance IL-12 receptor expression during therapy as a potential marker of a more efficacious protocol using both IL-12 and IFN alpha. The results of these studies will further improve our understanding of the mechanisms of action of IL- 12 and other cytokines and will assist in targeting a more potent combination of agents which can suppress clonal growth and correct abnormal antitumor immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
1K24CA081022-01A1
Application #
6129467
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
1
Fiscal Year
2000
Total Cost
$125,201
Indirect Cost
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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