Topical imiquimod and intralesional interleukin-2 increase activated lymphocytes and restore the Th1/Th2 balance in patients with metastatic melanoma.

Abstract

Patients with metastatic skin disease in malignant melanoma are difficult to treat, with unresectable lesions proving the biggest challenge. We have recently published data showing a significant clinical response in patients with multiple in-transit melanoma metastases treated with a combination of topical imiquimod and intralesional interleukin (IL)-2. Here we report the results of immunological analysis with the aim of highlighting correlations with our clinical findings. To investigate the systemic effects of our localized combination treatment in patients with accessible metastases of melanoma, and to correlate this with their clinical responses. The peripheral blood mononuclear cells of patients were collected at various time points throughout the treatment. Using antibodies to T-cell subsets we measured the changes in cell populations, and along with polyclonal stimulation, changes in cytokine production from these cells over a treatment course. We report an increase in the mean CD4/CD8 ratio from 2.78 to 3.54 with treatment (P < 0.01), and a rise in the percentage of CD25+ cells in the CD4+ population from 14.52% to 38.56%. Furthermore, staining with activation and T-regulatory markers showed that the majority of this population is activated T cells. Cytokine analysis on polyclonally stimulated peripheral blood mononuclear cells showed an increase in the ability of cells to produce interferon (IFN)-gamma over the treatment course, with an initial rise in the IFN-gamma/IL-5 ratio in five of six patients. The results of this study provide evidence that, in the majority of patients with in-transit metastases of melanoma, therapy with a combination of topical imiquimod and intralesional IL-2 induces a systemic immunological effect by reversing some of changes noted in patients with malignant disease.