A Personalized short-time Immunotherapy with Subcutaneous very low-dose Il-2 plus the Pineal Hormone Melatonin in advanced cancer patients with Persistent Lymphocytopenia

Abstract

Today, it is known that the prognosis of human neoplasms depends not only on the genetic characteristics of tumor cells, but also on the immunobiological response of patients. Moreover, despite its complexity, at present it is known that the antitumor immunity is generally suppressed by the macrophage system, and stimulated by T lymphocytes, with the only exception of regulatory T cells, which in contrast inhibit the anticancer immunity through the release of immunosuppressive cytokines, the most important of them is TGF-beta. Finally, it is known that lymphocytopenia may predict a negative prognosis in the advanced neoplasms, and a more negative significance is played by the occurrence of abnormally low values of lymphocyte-to-monocyte ratio (LMR), whose decline could depend on both lymphocyte decrease and monocyte increase. At present, the only cytokine able to enhance lymphocyte count still remains IL-2. Therefore, because of the negative prognostic significance of cancer-related lymphocytopenia, the use of IL-2 to correct cancer-related lymphocytopenia could constitute a new strategy in the immunotherapy of cancer. On these bases, a study was planned to evaluate the effects of a neuro-immunotherapeutic combination with SC very-low dose IL-2 in association with the antitumor immunostimulating pineal hormone melatonin (MLT) on lymphocyte count, and their persistence on time in a group of untreatable lymphocytopenic advanced cancer patients. The study included 14 lymphocytopenic cancer patients, who were eligible for the only palliative therapy. IL-2 was SC injected at 1.8 MIU/day for 5 days/week for 2 consecutive weeks, in association with MLT at 100 mg/day orally during the dark period of the day. A normalization of lymphocyte count was achieved in 9/14 (64%) patients within the two weeks of therapy. Both lymphocyte and LMR mean values significantly increased on therapy with respect to the pre-treatment values. On the other hand, monocyte mean values diminished on therapy, without, however, significant differences. The median duration of lymphocyte count normalization was 160 days (range 39-240 days). These preliminary results would suggest a new possible clinical use of IL-2 immunotherapy to counteract advanced cancer-related lymphocytopenia, because of its well documented negative effects on the survival, in an attempt to control tumor growth by activating the natural antitumor immunobiological response, which is fundamentally an IL-2-dependent phenomenon, and which is altered in the advanced human neoplasms. Keywords: Cancer immunotherapy, Interleukin-2, Lymphocytopenia, Immunosuppression, Melatonin, Pineal gland