IMMUNE-RESPONSE INDUCED IN SMALL-CELL LUNG-CANCER BY MAINTENANCE THERAPY WITH INTERFERON-GAMMA

Background: Chemotherapy, with or without radiotherapy, results in a 3 0%-40% complete response rate in small-cell lung cancer (SCLC), but ap proximately 90% of patients who have complete remission die within 2 y ears after relapse with chemoresistant disease. Randomized clinical st udies of maintenance chemotherapy after complete response have failed to demonstrate survival advantage. However, studies have shown that th e human cytokine interferon gamma (IFN-gamma) induces immune response in humans, including.T-cell activation and expression of class II majo r histocompatibility complex (HLA-DR) and receptor for the Fc portion of immunoglobulin on monocytes. It has also been demonstrated that rec ombinant IFN-gamma (rIFN-gamma) induces immunomodulation and has anti- proliferative activity. Purpose: In vivo effects of rIFN-gamma treatme nt were characterized by now cytometric analysis of peripheral blood m ononuclear cells in patients with SCLC who received rIFN-gamma as main tenance treatment. Methods: After induction chemotherapy and radiother apy, 100 patients who achieved a complete remission were randomly assi gned to receive rIFN-gamma at a dose of 0.2 mg (4 X 10(6) units) once a day, subcutaneously, for 6 months, or observation only. In 31 patien ts, peripheral mononuclear cells were obtained prior to the study and at weeks 4, 8, and 12 for serial monitoring of immune response. By flo w cytometric analysis, we identified the lymphocyte and monocyte popul ations using characteristic differences in electronic volume and right -angle scatter. In these populations, we determined the mean fluoresce nce channel after staining for CD14 (antigen expressed on monocytes), CD3 (antigen expressed on T lymphocytes), and HLA-DR (HLA class II exp ressed by monocytes and activated lymphocytes). To determine the numbe r of Fc receptors per cell, an Fc receptor assay was performed using t he monocyte cell line U937 as a standard. Results: At weeks 4, 8, and 12, expression of HLA-DR and Fe receptors on monocytes in patients who received rIFN-gamma was significantly higher than that in untreated p atients, and the difference was statistically . significant. The numbe r of Fc receptors per monocyte consistently increased during the rIFN- gamma treatment and reached a fivefold elevation at week 12. There was no statistically significant difference in lymphocyte surface antigen expression between the treated and untreated groups. Conclusion: The dose of rIFN-gamma used in this study resulted in immune stimulation i n patients with SCLC who had complete remission after induction therap y. The in vivo immunomodulatory activity of rIFN-gamma in such patient s is characterized by a strong monocyte activation but no significant alteration in T-cell activation.