Treatment of Advanced Cancer-related Lymphocytopenia: Comparison among the Effects of Subcutaneous Low-dose Interleukin-2, High-dose Pineal Hormone Melatonin and Checkpoint Inhibitors

Abstract

Background: Despite the negative prognostic significance of lymphocytopenia is known for many years no clinical cancer study has been proposed up to now in an attempt to specifically correct the evidence of an abnormally low lymphocyte count. At present it is known that IL-2 is the main growth factor for T lymphocytes. Lymphocyte proliferation is also stimulated by the pineal indole hormone melatonin (MLT), which is provided by an anticancer activity, whereas it is inhibited by cortisol.Objective: On this basis a preliminary study was carried out to evaluate which may be the optimal therapeutic schedule of cancer-related lymphocytopenia. Methods:The study included 40 advanced solid tumor patients who were treated by the best supportive care (BSC) (n=9), high-dose MLT alone (n=12) at 100 mg/day in the night, subcutaneous low-dose IL-2 alone (n=9) at 1.8 MIU/day for 5 days/week for 2 weeks followed by 2 weeks-rest period, or IL-2 plus MLT. The duration of study was 6 weeks. Results:The results were compared to those found in 10 advanced cancer patients treated by the checkpoint inhibitor Nivolumab (NVB) at 3 mg/kg/b.w. every 15 days. Lymphocyte count rapidly increased in a significant manner on IL-2 therapy, and a greater increase was reached by Il-2 + MLT. Lymphocyte mean count also increased on MLT alone and on NVB, without, however any statistically significant increase. Finally lymphocyte mean count progressively decreased on BSC alone.Conclusions: This preliminary study shows that S.C. low-dose IL-2 is the only drug able to rapidly correct cancer-related lymphocytopenia, whose efficacy may be further amplified by the concomitant endocrine therapy with the pineal hormone MLT. Further studies will be required to evaluate the impact of the lymphocytopenia correction on the survival of advanced cancer patients.

A Phase-2 Study on the Kinetics of the Improvement in Lymphocyte-toMonocyte Ratio by High-Dose Pineal Hormone Melatonin in Lymphocytopenic Untreatable Metastatic Cancer Patients

“…Even though with a lower efficacy and in less rapid manner with respect to the results obtained with IL-2 [17][18][19][20], this preliminary study shows that high-dose MLT may be also effective in the treatment of cancer-related lymphocytopenia in patients with disseminated cancer, and for whom no other conventional antitumor therapy was available. Obviously, randomized studies will be required to confirm these results.…”

The Potential of Integrative Cancer Treatment Using Melatonin and the Challenge of Heterogeneity in Population-Based Studies: A Case Report of Colon Cancer and a Literature Review

“…The anticancer potential of Mel has been shown in many experimental works [16,17,115,116]. The mechanisms of antitumor activity of Mel are associated with pleiotropic effects on cancer cells and the tumor microenvironment, including the induction of apoptosis; anti-inflammatory, anti-angiogenic, antiproliferative, and antimetastatic action; and the regulation of the immune and psychoneuroendocrine systems [33,71,104,115,[117][118][119][120][121][122][123][124][125][126][127][128].…”

“…In clinical studies by Lissoni et al, patients have taken oral Mel at high daily doses (≥20 mg) [70,71,88,89,[118][119][120][121]125,136]. A favorable effect on the survival of patients with prostate cancer has been reported at a dose of 3 mg/day [137].…”

“…Mel supplementation (20 mg/day) after 6 months did not affect NK cell cytotoxicity or phenotype, nor did it affect blood levels of inflammatory cytokines in patients with NSCLC [141]. The combination of IL-2 and Mel may stabilize the disease and increase the survival of patients with metastatic tumors [125][126][127]144]. The survival of patients with solid tumors and brain metastases who received RT of the brain was studied.…”

Relevance of Further Clinical Trials of the Use of Melatonin in Adjuvant Cancer Therapy

“…Так, М, введенный совместно с интерлейкином-2, улучшает терапевтический эффект последнего, увеличивая количество лимфоцитов и эозинофилов. Эта комбинация увеличивает продолжительность жизни пациентов с устойчивыми к терапии метастатическими опухолями [25][26][27][28]. Кроме того, исследователи отмечают, что стандартная ХТ опухолей совместно с М вызывает регрессию опухолей в большей мере, чем без него [15,16,29].…”