Efficacy of Melatonin in the Immunotherapy of Cancer Using lnterleukin-2

Abstract

Recent experimental and clinical observations have suggested that host antitumor immunobiological resistance is generated by interactions between cytokines and immunomodulating hormones. In particular, it has been shown that the pineal hormone melatonin (MLT), whose oncostatic and immunomodulating activities have been well documented, may enhance the in vivo antitumor efficacy of interleukin-2 (IL-2). This study reports the results obtained up to now in untreatable advanced solid tumor patients, treated by neuroimmunotherapy with low-dose IL-2 plus MLT. The study included 342 advanced solid tumor patients with a life expectancy of less than 6 months who had not responded to previous chemotherapy or who were affected by neoplasms for which no effective standard therapy is available. Non-small cell lung cancer and gastrointestinal tract tumors were the neoplasms most frequently detected in our patients. IL-2 was given subcutaneously at 3 million IU/day in the evening for 6 days/week for 4 weeks, corresponding to one cycle. MLT was given orally at 40 mg/day in the evening, every day starting 7 days prior to IL-2. In nonprogressing patients, a second cycle was repeated after a 21-day rest period; then, patients underwent a maintenance treatment consisting of 1 week of therapy every month until progression. Patients were considered as evaluable when they received at least one cycle. Of the 342 patients, 320 were evaluable. Objective tumor regressions were achieved in 53/320 (17%) patients, consisting of four complete responses and 49 partial responses. The median duration of response was 9 months. Most responses were observed in lung cancer, hepatocarcinoma, pancreatic cancer, gastric cancer, and endocrine tumors. A survival longer than 1 year was achieved in 128/320 (40%) patients, and the percentage rate of survival at 1 year was significantly higher in the responders than in the nonresponders. Toxicity was low in all patients, fever being the only relevant side-effect This pilot clinical study shows that the concomitant administration of the pineal hormone MLT may make IL-2 effective in advanced solid tumors which generally do not respond to IL-2 alone, and suggests that the application of psychoneuroimmune knowledge to IL-2 cancer immunotherapy may represent a promising new strategy to enhance the clinical efficacy of cancer biotherapies with cytokines.