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.
OBJECTIVE
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.


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.
Division of Radiation Oncology, S. Gerardo Hospital, 20052 Monza (Milan), Italy.
Paolo
P
Lissoni
Fabio
F
Malugani
Ola
O
Malysheva
Vladimir
V
Kozlov
Moshe
M
Laudon
Ario
A
Conti
Georges
G
Maestroni
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000556:secondary; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000556:secondary; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D018847:Opioid Peptides / Q000187:drug effects / Q000276:immunology; D010865:Pilot Projects
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D007376:Interleukin-2; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D009271:Naltrexone; D008550:Melatonin