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including Psychoneuroimmunology, Neuro
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ISSN 0172–780X

NEL Vol.23 No.4, August 2002

Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous low-dose interleukin-2, melatonin and naltrexone

2002; 23:341344
pii: NEL230402A09
PMID: 12195238

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Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous low-dose interleukin-2, melatonin and naltrexone: Modulation of interleukin-2-induced antitumor immunity by blocking the opioid system
Paolo Lissoni 1, Fabio Malugani 1, Ola Malysheva 2, Vladimir Kozlov 2, Moshe Laudon 3, Ario Conti 4 & Georges Maestroni 4

1. Division of Radiation Oncology, S. Gerardo Hospital, Monza (Milan), Italy.
2. Institute of Clinical Immunology, Russian Academy of Medical Sciences, Novosibirsk, Russia.
3. Neurim Pharmaceuticals, Tel-Aviv, Israel.
4. Institue of Pathology, Locarno, Switzerland.

Key words:
interleukin-2; melatonin; naltrexone; neuroimmunotherapy

Submitted: July 29, 2002
Accepted: July 30, 2002


OBJECTIVES: The preliminary applications of the psychoneuroimmunological knowledges to the treatment of human diseases have confirmed the possibility to amplify IL-2-dependent anticancer immunity by the pineal hormone melatonin (MLT) or by opioid antagonist, such as naltrexone (NTX), which act by activating TH1 lymphocytes or suppressing TH2 lymphocytes, respectively. At present, however, there are no data about the immunobiological effects of a concomitant administration of both MLT and NTX on IL-2-induced anticancer immunity. This preliminary study was carried out to evaluate whether the association of NTX may further enhance the lymphocytosis induced by the neuroimmunotherapy with IL-2 plus MLT.

MATERIALS & METHODS: The study included 14 consecutive untreatable metastatic solid tumor patients. According to a cross-over randomized study, the patients were treated during two consecutive immunotherapeutic cycles at 21-day intervals with IL-2 plus MLT alone or with IL-2 plus MLT plus NTX. IL-2 was injected subcutaneously at 3 MIU/day for 6 days/week for 4 weeks, MLT was given orally at 20 mg /day in the evening every day, and NTX was given orally at 100 mg in the morning every next day. For the immune evaluation, venous blood samples were drawn before the onset of treatment and at weekly intervals.

RESULTS: Lymphocyte mean number significantly increased after both IL-2 plus MLT and IL-2 plus MLT plus NTX. However, the concomitant administration of NTX induced a significantly higher increase in lymphocyte mean number with respect to that achieved with IL-2 plus MLT alone. In contrast, the increase in eosinophil mean number was significantly higher on IL-2 plus MLT alone.

CONCLUSIONS: This preliminary study shows that the association of NTX further amplifies the lymphocytosis obtained by IL-2 plus MLT. Since the lymphocytosis represents the most important favourable prognostic variable predicting the anticancer efficacy of IL-2 immunotherapy, it is probable that a cancer neuroimmunotherapy with IL-2 plus both MLT and NTX to activate TH1 and suppress TH2 cells respectively, may deserve more promising results in the treatment of human neoplasms according to the psychoneuroimnunological knowledge.



After several years of experimental and clinical studies, at present it is known that the immune system may mediate both activation and suppression of the immunological response against cancer growth [1–4]. The activation of the anticancer immunity would be namely mediated by T helper-1 (TH1) lymphocytes through the release of interleukin-2 (IL-2) [1,2], whereas its suppression is depending on the activation of T helper-2 (TH2) lymphocytes, which release interleukin-10 (IL-10), that has been proven to block IL-2 secretion and IL-2-induced generation of cytotoxic lymphocytes [3,4]. The lymphocytes have appeared to express receptors for several neurohormones and neuropeptides [5,6], and this evidence would explain the influence of the psychoemotional status on the immune system, including the anticancer immunity [5,7]. Within the neuroendocrine system, the pineal hormone melatonin (MLT) would represent one of the major neuroactive substances responsible for TH1 activation [7–10] with a consequent stimulation of the anti-cancer immunity [1], whereas TH2 activation would be mainly under an opioid stimulatory control [11], particularly mediated by the m-opioid receptor. Therefore, the opioid stimulation would suppress the anticancer immunity by activating TH2 lymphocytes [11]. In fact, in experimental conditions, the long-acting opioid antagonist naltrexone (NTX) has been proven to induce immunostimulation by determining an enhanced IL-2 production and a diminished IL-10 secretion [11]. On the other side, the concomitant administration of MLT has appeared to amplify the biological effects of IL-2 in cancer patients [12]. Finally, preliminary studies in cancer patients would suggest that the administration of NTX may also enhance the immunobiological effects of IL-2 [13]. At present, however, there are no data about the influence on IL-2 activities of a concomitant administration of both MLT and NTX in an attempt to activate TH1 and to suppress TH2 lymphocytes, respectively. Therefore, at present it is still unclear whether the concomitant activation of TH1 cells by MLT and the suppression of TH2 cells by NTX may further amplify IL-2-induced anticancer immunobiological functions with respect to each single strategy with MLT alone or NTX alone. The present study was performed to analyze the immunobiological effects of IL-2 plus MLT with or without a concomitant NTX administration in patients with metastatic solid neoplasms.

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