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
ABSTRACT
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.
Introduction
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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