A new neuroimmunotherapeutic strategy of subcutaneous low-dose interleukin-2 plus the long-acting opioid antagonist naltrexone in metastatic cancer patients progressing on interleukin-2 alone.
OBJECTIVE
Recent advances in knowledge of Psychoneuroimmunology have shown that several neuroactive substances, including neurohormones and neuropeptides, may exert immunomodulatory effects. However, despite the great variety of potential neuroimmune interactions, at present we may recognize two major neuroendocrine systems exerting a physiological neuroimmunomodulatory function, consisting of the pineal gland and the brain opioid system, provided by immunostimulatory and immunosuppressive effects, respectively. Recent in human studies have demonstrated the possibility to amplify the biological activity of IL-2, the major anticancer cytokine, by pineal indoles.


METHODS
The present study was carried out to draw some preliminary in human results on the possible immunomodulatory effects of the inhibition of the brain opioid activity by a long-acting opioid antagonist, naltrexone (NTX). The study was performed in 10 metastatic renal cell cancer patients, who had progressed on a previous immunotherapeutic cycle with IL-2 alone. Patients were treated with the same doses of IL-2 (6 million lU/day subcutaneously for 6 days/week for 4 weeks) plus an oral administration of NTX at a dose of 100 mg every 2 days.


RESULTS
The clinical response consisted of a partial response in 1 and a stable disease in 5 patients, whereas the other 4 patients progressed. Therefore, the percent of non-progressive disease was 6/10 (60%). Moreover, mean lymphocyte increase achieved during IL-2 plus NTX was significantly higher (P<0.05) than that obtained during the previous treatment with IL-2 alone.


CONCLUSIONS
This study shows that a blockade of the brain opioid system, which plays a physiological immunosuppressive role, may improve the anticancer effects of IL-2 in humans.
Lissoni
Paolo
P
Division of Radiation Oncology, S. Gerardo Hospital, Monza, Milan, Italy.
Malugani
Fabio
F
Bordin
Veronica
V
Conti
Ario
A
Maestroni
George
G
Tancini
Gabriele
G
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000556:secondary; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D015213:Neuroimmunomodulation / Q000187:drug effects; D010865:Pilot Projects
D000970:Antineoplastic Agents; D007376:Interleukin-2; D009292:Narcotic Antagonists; D009271:Naltrexone