Cutaneous T-cell lymphoma (CTCL) is a clonally derived, skin invasive malignancy of CD4+ T lymphocytes with the phenotype of mature helper T- cells. The applicant's 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. He has also demonstrated increased production of T-helper type 2 (Th2) cytokines (IL-4, IL-3) and deficient production of Thl 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, he has initiated a phase I trial of IL-12 conducted in his institution's GCRC to treat 24 patients with CTCL. The early data indicate that IL-12 has marked therapeutic activity with 4/7patients having significant clinical and histological responses and 2/7 having complete responses. In this application, the applicant will focus on understanding the in vivo mechanisms of action of IL-12 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. He 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. He will also examine IL-12 receptor expression prior to and prospectively during therapy to determine if down-modulation of receptors accounts for tolerance to the clinical effects of IL-12. Since his preliminary data indicate that IFN alpha up-regulates IL-12 receptor expression on the peripheral blood cells of CTCL patients, he 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 understanding of the mechanisms of action of IL-12 and will assist in targeting a more potent combination of agents, which can suppress clonal growth and correct abnormal anti-tumor immunity.
| Suchin, Karen Rebecca; Cucchiara, Andrew J; Gottleib, Scott L et al. (2002) Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 138:1054-60 |
| Geng, Y; Shane, R B; Berencsi, K et al. (2000) Chlamydia pneumoniae inhibits apoptosis in human peripheral blood mononuclear cells through induction of IL-10. J Immunol 164:5522-9 |
