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Modulation of Immune and Anti-Tumor Effects of Cancer Immunotherapy with Anti-Pd-1 Monoclonal Antibodies by the Pineal Hormone Melatonin: Preliminary Clinical Results

The recent cancer immunotherapy with inhibitors of the expression of PD-1 and its ligands represents one of the most promising strategies in cancer cure. Then, the main question is how to enhance its therapeutic efficacy, which could potentially achieved by its association with chemotherapy, Il-2 immunotherapy, and anti-angiogenic strategies. By taking into consideration that the immune system is physiologically under a neuroendocrine regulation, another possible strategy to enhance the efficacy of cancer immunotherapy could consist of a neuro immune approach, namely by the pineal hormone melatonin (MLT), which at present constitutes the most investigated endogenous neuroendocrine molecule provided by immune stimulatory anticancer properties. On these bases, a study was planned to evaluate the effects of a concomitant administration of high-dose MLT in metastatic cancer patients treated by the anti-PD-1 monoclonal antibody Nivolumab (NIVO). The study included 14 patients, and the results were compared to those observed in a control group of 50 patients. No small cell lung cancer and melanoma were the most frequent tumor histo types. MLT was given orally at 100 mg/day during the dark period of the day, and NIVO was injected i.e. at 3 mg/kg b.w. at 15-day intervals. The percentage of both objective tumor regressions and disease control (DC) were higher in patients concomitantly treated by MLT, even though the only difference in DC was statistically significant. This evidence was associated with a significantly higher increase in lymphocyte-to-monocyte ratio (LMR) in MLT group, by suggesting that MLT may be successfully associated with anti-PD-1 monoclonal antibodies to pilot the immune response in an antitumor way by stimulating lymphocyte proliferation and inhibiting macrophage-induced inflammatory status, which suppresses the antitumor immunity.