Immunotherapy with Mistletoe Lectin-1:
A Scientific Approach in Complementary Oncology
by Josef Beuth, M.D.
Institute of Medical Microbiology and Hygiene,
University of Köln, Goldenfelsstr. 19-21, 50935 Köln, Germany
Complementary medicine:
a scientific approach to comprehensive therapy in oncology
The concept of scientific complementary medicine arose from the growing
awareness that cytotoxic tumor destructive therapies (e.g. radiotherapy,
chemotherapy) obviously fail to provide a reasonable benefit for patients
suffering from carcinomas. Although the toxicity of chemo/ radiotherapeutic
regimens was ultimately increased, demanding stem cell transplantation and
other cost-intensive supports, no statistically evaluable benefit on overall
survival could be observed for most patients with advanced carcinomas. These
disappointing data and missing therpeutical options finally resulted in
the definition of criteria other than survival to suggest a therapeutical
benefit. Accordingly, remission rate (further specified in complete/partial
remission) was postulated to correlate with therapeutical success, however,
biometric meta-analyses totally neglected this correlation. Some studies
even demonstrated inverse correlations between remission and patient survival,
however, it is still established as a marker of therapeutical success.
Whereas conventional cytotoxic tumor destructive strategies (chemo/radiotherapy)
are well appreciated for most pediatric tumor entities as well as for primarily
systemic neoplastic diseases (e.g. leukemias, lymphomas) and defined non-carcinomatous
neoplasmas (e.g. of testicular origin) most epithal derived cancers (= carcinomas)
do not reasonably respond. Especially asymptomatic patients with advanced
carcinomas after surgical treatment do not profit from adjuvant cytotoxic
treatment, except for defined tumor entities and stages. This conclusion
can be drawn from biometric analyses by U. Abel and R. Moss who demonstrated
currently that most standard chemotherapeutic schedules lack adequate scientific
evaluation. Surely, most cytotoxic treatment modalities were not evaluated
in accordance to good clinical practic (GCP), however, influential industry
driven interests delay an important change of paradigma.
This great task has been taken over by the scientific complementary medicine
and was immediately promoted by the German Society of Oncology (GSO). Diverse
statements of the GSO clarified that complementary medicine is by no means
an alternative to tumor destructive therapies but an addition. Currently,
several projects of the scientific complementary medicine are being evaluated
in prospectively randomized clinical studies (e.g. immunomodulating mistletoe
lectin-1; lectin blocking to prevent metastasis; induction of cell differentiation;
active-specific immunotherapy/tumor cell vaccination; defined antioxidant
supplementation; psycho-oncologic guidance, hyperthermia, nutritional advice
etc.) and the orthodox oncology should also follow scientific evaluation
standards as to save its reputation.
Immunomodulatory activity of mistletoe
lectin-1 (ML-1)
The scientific evaluation of the immunomodulatory efficacy of the galactoside-specific
lectin from mistletoe (mistletoe lectin-1, ML-1) was recently initiated.
Promising results have been found in vitro and comprise the upregulation
of immune cell activation markers and cytokine release (10), downregulation
of tumor cell proliferation and tumor spheroid growth (13) as well as pronounced
dose-dependent cytotoxicity towards various cell lines (2). In vivo, regular
subcuanteous administration of a defined ML-1 dosage (1 ng/kg body weight,
twice a week) yielded enhanced thymocyte proliferation, maturation and emigration
(3), significantly increased peripheral blood immune cell counts and activities
(22), immunorestoration after steroid application (4) as well as significant
antimetastatic (5) and antibacterial effects (23) in different murine models.
These promising experimental data encouraged the non-study based administration
of ML-1 standardized mistletoe extract to cancer patients. All patients
were subcutaneously injected with 1 ng ML-1/kg body weight, twice a week
over a 4-5 weeks' periode. This ML-1 concentration was shown to be optimal
in preceeding experiments (6), the time schedule was fixed after recommendations
from a scientific board. However, optimal ML-1 dosage and application schedule
for immunopotentiation in cancer patients obviously warrant reconsideration
since prolongation of treatment interval as well as administration of higher
ML-1 concentrations yielded beneficial effects in experimental in vivo models
(14). In cancer patients 1) significantly increased counts and activities
of peripheral blood lymphocytes and natural killer (NK)-cells (7), 2) increased
serum levels of acute phase reactants (8), 3) enhanced delayed type of hypersensitivity
after intracutaneous challenge (9), 4) increased serum levels of ß-endorphin
(10) and 5) improved quality of life (11) could be reproducibly demonstrated
after ML-1 treatment as proposed. These (pre)clinical data were the basis
for more advanced clinical studies following prospectively randomized designs.
Tumor entities, complementary treated with ML-1 standardized mistletoe extract,
included glioblastoma multiforme, breast and colorectal carcinoma. Primary
aims of these trials, as fixed in the study protocols, were improvement
of quality of life (determined by adequate questionnaires and confirmed
by measurement of ß-endorphin plasma levels) and immunoprotection.
Secondary aims to be evaluated during/after immunotherapy included influence
on side effects of tumordestructive treatment (chemotherapy), metastasis/relapse
rate and overall survival.
Glioblastoma multiforme
Astroglial brain tumors (e.g. glioblastoma multiforme) are the most common
primary brain tumors. Neurosurgery and radiotherapy represent the only tumor
destructive therapeutical approaches and are still lacking convincing evidence
of their benefit. The administration of (neo)adjuvant chemotherapy is still
controversial since it has not resulted in biometrically evaluable prolongiation
of survival time (16, 19). In spite of progress in these techniques only
a moderate improvement of overall survival has been achieved over the past
decade.
Generally, tumor destructive therapies induce immunosuppression. A prospectively
randomized clinical trial with patients suffering from malignant glioma
stage III/IV (n = 35) was performed to evaluate a) the immunosuppressive
effects of standard tumor destructive therapy b) the immunoprotective efficacy
of complementary immunotherapy with ML-1 standardized mistletoe extract
and c) the benefit of immunotherapy to qualitiy of life.
As recently shown for other tumor entities (e.g. colorectal and breast
carcinoma; 10, 11) tumor destructive therapy of stage III/IV malignant glioma
(neurosurgery, perioperative cortisone treatment, local radiation postoperatively)
proofed to be immunosuppressive, especially down regulating peripheral blood
lymphocytes but not granulocytes and monocytes. Flow cytometry (FACS, Fluorescence-activated
cell sorting) revealed that counts of T-cell subsets (e.g. CD-3+, CD-4+,
CD-8+, CD-3+/C-16+, CD-56+), B-cells, and NK-cells as well as T-cell activities
(e.g. CD-25+, HLA/DR+) were significantly down regulated after primary treatment.
During the study patients of the control and study groups were regularly
monitored concerning the cellular immune system. The significant postoperative
downregulation of counts and activities of lymphatic cells was followed
by recovery to almost preoperative values in the control group after 3-6
months. However, regular subcutaneous administration of the defined immunomodulating
dosage of ML-1 (1 ng/kg body weight, twice a week, for 3 months) induced
a considerable upregulation of lymphocyte counts and activities which was
statistically significant (as compared to preoperative control values) for
CD-3+, CD-4+, CD-8+, CD-25+ and HLA/DR+ T-cells after 3 months of treatment
(15).
In an attempt to demonstrate the clinical benefit of immunotherapy with
ML-1 standardized mistletoe extract, quality of life was assessed by standard
questionnaire (Spitzer). Although no obvious difference between control
and study group could be shown initially (3 months postoperatively) patients
of the ML-1 treated verum group presented a considerably higher questionnaire
score (correlating with an improved quality of life) after a 6 months follow
up period, as compared to patients of the control group (15). Accordingly,
a co-stimulation of the neuro-immuno-endocrine system was anticipated and
further confirmed for breast carcinoma patients, as shown below.
Breast carcinoma
Breast carcinoma is the most frequent female malignancy. Treatment strategies
include surgery, chemo/radio/hormonal therapy, however, convincing evidence
for biometrically verifiable benefits (e.g. increased overall survival)
is still lacking for most patients. This disappointing therapeutic success
resulted in conception of high dose chemotherapy regimes demanding stem
cell transplantation and other cost-intensive supports, however, no proof
of efficacy is available for this option so far (17). Criteria other than
survival were recently suggested to demonstrate therapeutical benefit, e.g.
remission rate which was postulated to correlate with prolongation of overall
survival. However, biometric meta-analyses totally neglected this correlation,
some studies even demonstrated inverse correlations between remission and
patient survival (1).
To increase the therapeutical efficacy of tumor destructive regimes,
scientifically based immunomodulation with ML-1 standardized mistletoe extract
was introduced. The aim of this initial study with breast carcinoma patients
was to assess whether this complementary treatment can favourably affect
immunological/neuroendocrinological parameters. Accordingly, patients (control
group n = 32, therapy group n = 36) with histologically verified breast
carcinoma (TNM stages III, IV) were enrolled in this study. All patients
were surgically treated and hospitalized for chemotherapy (both according
to standard protocols).
To correlate critically empirical clinical observations (stabiliziation
of mood, perception of pain) with the administration of mistletoe extract
standardized for ML-1, ß-endorphin plasma levels of the patients were
determined and compared to non-immunomodulated patients. Prior to ML-1 treatment
the mean ß-endorphin plasma level of non ML-1 treated patients (6.32
pg/mL), and ML-1 treated patients (7.46 pg/mL) were comparable, both within
the normal range (3-10 pg/mL).
To further analyze the neuro-immunological activity of ML-1, breast carcinoma
patients were divided after treatment into therapeutical responders (n =
25) and non-responders (n = 11). This procedure proofed to be favourable
since ML-1 responders presented an evidently improved quality of life (as
determined by standard questionnaire). Furthermore, therapeutical responders
presented an enhanced activity of defined immune parameters (cytokin release,
peripheral blood lymphocyte counts) and a positive skin reaction (rubor,
infiltration) at the injection site wheras non-responders did not present
any of these reactions. Separation of responders/non-responders to ML-1
treatment appeared to be of relevance since after 6/12 weeks of application
the mean ß-endorphin plasma levels of responders (13.6/14.6 pg/mL)
were statistically significantly (p < 0.005) different from 1) basic
ß-endorphin plasma levels of this group of patients (7.46 pg/mL) 2)
ß-endorphin plasma levels of control patients without ML-1 treatment
(6.03/7.32 pg/mL) 3) ß-endorphin plasma levels of non-responders (6.22/6.46
pg/mL).
The increased ß-endorphin plasma levels in the responder group
after ML-1 administration correlated positively with enhanced in vitro cytokin
release (Il-2, TNF-(, IFN-() by mononuclear cells of these patients. Furtheron,
peripheral blood lymphocyte subset counts also correlated with ß-endorphin
plasma levels after ML-1 treatment. As compared to the control group of
patients, complementary ML-1 application induced an increase of all lymphocyte
subpopulations (10).
In the course of another prospectively randomized clinical trial with
breast carcinoma patients (n = 47, histologically verified, TNM stages III/IV)
ß-endorphin plasma levels were correlated to NK-cell and T-lymphocyte
activities by analysis of SPEARMAN correlation coefficient (12). This investigation
definitely suggested a close correlation of defined cellular immune parameters
(NK-cell, T-lymphocyte activities) and plasma ß-endorphin levels and
further demonstrates the close correlation of the immuno-neuro-endocrine
axis (10, 12, 18). Obviously, complementary ML-1 treatment modulates defined
immune functions (involved in antitumor/antimicrobial resistance) and neuroendocrine
functions (determining the quality of life) in cancer patients and may thus
be beneficial for those patients.
Colorectal carcinoma
Colorectal carcinoma is one of the commenest cancers in the developed
countries, affecting more males than females (21). In the treatment of this
malignancy and ist metastatic spread, including surgery, chemotherapy and
radiotherapy, little progress has been achieved over the last decade. Approximately
50% of patients who develop colorectal carcinoma do not survive 5 years,
although surgery with curative intent is possible in about 80% of all cases.
In order to reduce the high mortality rate, complementary treatment modalities
are warranted to improve the prognosis for these patients (20).
A prospectively randomized clinical study was initiated to investigate
the efficacy of ML-1 standardized mistletoe extract application on defined
effects on patients with advanced colorectal carcinoma. A total of 79 patients
were enrolled into this study and treated on standard protocol with 5-FU
(Fluorouracil) and FA (Folinicacid). Patients were randomized into control
group (n = 41, no complementary treatment) and verum group (n = 38; complementary
treated with ML-1 standardized mistletoe extract, 1 ng/kg body weight, twice
a week for 8 weeks followed by a 4 weeks break) following the "matched
pairs" design. Analysis of peripheral blood cells (including lymphocyte
subsets and activities by flow cytometry), therapy/disease-induced side
effects, length of remission, overall survival and quality of life (FACT:
Functional Assessment of Cancer Therapy Scale V 3.0) was regulary accomplished.
Concerning the primary aim of this study the quality of life (assessed
in 6 weeks turns), a significant improvement was established for ML-1 treated
patients as compared to control group patients. Since this beneficial effect
of complementary immunotherapy reached statistical significance not earlier
than 12 weeks, a placebo effect can be ruled out. A non therapy-induced
improvement of the qualitiy of life apparently would have been detectable
in the early phase of treatment (11). Although the late onset of improvement
of quality of life is a strong indication for the beneficial efficacy of
ML-1 treatment, a placebo-controlled confirmative study is necessary for
definite proof.
Evaluation of therapy-induced side effects demonstrated an evident benefit
for complementary ML-1 treated patients. As compared to rate and severity
of side effects in the control group of patients, those of the verum group
suffered significantly less from leukopenia and mucositis (WHO grade III).
Furtheron, duration of severe mucositis was significantly reduced, however,
no significant effect of ML-1 administration could be verified on frequency
and length of remission, relapse-free interval and overall survival (11).
Since improvement of quality of life and reduction of side effects were
the primary variables of the design of this prospectively randomized clinical
study, the benefit for complementary ML-1 treated colorectal carcinoma patients
is obvious.
Conclusion
Further prospectively randomized clinical multicenter studies are currently
under investigation to confirm the beneficial efficacy of complementary
treatment with ML-1 standardized mistletoe extracts on oncological patients
suffering from ENT (ear-nose-throat), breast and bladder carcinoma. So far
no definite conclusion can be drawn from these studies because of the still
ongoing follow up. However, the promising data of the presented prospectively
randomized clinical trials suggest that ML-1 standardized mistletoe extract
can be recommended for the tumor entities tested so far.
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