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
Paolo
Lissoni 1, Fabio Malugani 1, Veronica Bordin 1, Ario Conti
2, George Maestroni 2 & Gabriele Tancini 1
1.
Division of Radiation Oncology, S. Gerardo Hospital, Monza,
Milan, ITALY.
2. Institute of Pathology, Locarno, SWITZERLAND.
Submitted:
February 1, 2002
Accepted: March 6, 2002
Keywords:
immunotherapy; interleukin-2; naltrexone; neuroimmunomodulation;
opioid system
Abstract
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.
MATERIALS
& 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.
Introduction
Recent advances in knowledge of neuroimmunomodulation (NIM)
have shown that most neurohormones and neuropeptides may play
immunomodulatory effects on lymphocyte and macrophage functions
by acting on specific neurohormonal and neuropeptidergic receptors
expressed by the immune cells [1,2]. Unfortunately, most immunomodulating
effects played by neuropeptides and neurohormones are extremely
varied, depending on dose, way of injection, experimental conditions
and psychoneuroendocrine status of the investigated subjects.
Therefore, it is still difficult to translate in vivo the great
variety of immunomodulatory effects described in vitro. Then,
the definition of the physiological significance of NIM is still
at the beginning. However, despite the controversial experimental
data, at present it has been already possible to demonstrate
that the endogenous opioid system, particularly through the
mu-opioid receptors, plays a major immunosuppressive role, namely
on cellular immunity, including the antitumor immune response
[3]. Even though the mechanisms responsible for the immunosuppressive
role of the opioid agents are still unclear, it has been shown
that the opioids may induce immunosuppression namely by inhibiting
T helper-1 (TH1) lymphocyte functions and stimulating T helper-2
(TH2) lymphocyte activity [3]. Since the anticancer immunity
is a TH1 dependent phenomenon, whereas the TH2 activity inhibits
antitumor immune response [4, 5], the inhibition of TH1 functions
and activation of TH2 lymphocytes by the opioid agonists may
allow a suppression of immune reactions against cancer growth.
TH1 lymphocytes stimulate the anticancer immunity namely through
the release IL-2, which is the main anticancer cytokine, whereas
TH2 lymphocytes immunosuppress the antitumor immunity mainly
through the secretion of IL-10, which exerts immunosuppressive
effects by inhibiting secretion and activity of IL-2 itself
[4, 5]. The altered TH1/TH2 ratio, ... ...
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Material and methods
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