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.


References

1. Abel U: Chemotherapie fortgeschrittener Karzinome. Hippokrates Verlag Stuttgart, 1995.

2. Beuth J, Ko HL, Tunggal L, Jelaszewicz J, Steuer MK, and Pulverer G: Einfluß von wäßrigen, auf Mistellektin-1 standardisierten Mistelextrakten auf die in vitro (Tumor)Zellproliferation. Dtsch Zschr Onkol 1994; 26: 1-6.

3. Beuth J, Ko HL, Tunggal L, Steuer MK, Geisel J, Jelaszewicz J, and Pulverer G: Thymocyte proliferation and maturation in response to galactoside-specific mistletoe lectin-1. In vivo 1993; 7: 407-410.

4. Beuth J, Ko HL, Tunggal L, Buss G, Jeljaszewicz J, Steuer MK, and Pulverer G: Immunoprotective activity of the galactoside-specific mistletoe lectin in cortisone treated BALB/c-mice. In vivo 1994; 8: 989-992.

5. Beuth J, Ko HL, Gabius H-J, and Pulverer G: Influence of treatment with the immunomodulatory effective dose of the ß-galactoside-specific lectin from mistletoe on tumor colonization in BALB/c-mice for two experimental models. In vivo 1991; 5: 29-32.

6. Beuth J, Ko HL, Tunggal L, Buss G, Jeljaszewicz J, Steuer MK, and Pulverer G: Immunaktive Wirkung von Mistellektin-1 in Abhängigkeit von der Dosierung. Arzneimittel Forschung/Drug Research 1994; 11: 1255-1258.

7. Beuth J, Ko HL, Gabius H-J, Burrichter H, Oette K, and Pulverer G: Behavior of lymphocyte subsets and expression of activation markers in response to immunotherapy with galactoside-specific lectin from mistletoe in breast cancer patients. Clin Investig 1992; 70: 658-661.

8. Beuth J, Gabius H-J, Steuer MK, Geisel J, Steuer M, Ko HL, and G.Pulverer: Einfluß der Mistellektintherapie auf den Serumspiegel definierter Serumproteine (Aktuphaseproteine) bei Tumorpatienten. Med Klinik 1993; 88: 287-290.

9. Beuth J, Ko HL, and Pulverer G: Immunreaktion vom verzögerten Typ unter lektinoptimierter Misteltherapie bei Tumorpatienten. Dtsch Zschr Onkol 1995; 27: 130-133.

10. Heiny BM, and Beuth J: Mistletoe extract standardized for the galactoside-specific lectin (ML-1) induces ß-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res 1994; 1339-1342.

11. Heiny BM, Albrecht V, and Beuth J: Lebensqualitätsstabilisierung durch Mistellektin-1 normierten Extrakt beim fortgeschrittenen kolorekatalen Karzinom. Onkologe 1997; in press.

12. Heiny BM, Albrecht V, and Beuth J: Correlation of immune cell activities and ß-endorphin release in breast carcinoma patients treated with galactoside-specific lectin standardized mistletoe extract. Anticancer Res 1997; in press.

13. Lenartz D, Herrmann S, Pietch T, Rommel T, Menzel J, and Beuth J: Cytotoxic activity of the galactoside-specific lectin from mistletoe on anaplastic glioma cell spheroids and cell growth. Z Onkol/ J of Oncol 1997; 29: 11-15.

14. Lenartz D, Andermahr J, Menzel J, and Beuth J: Efficiency of treatment with galactoside-specific lectin from mistletoe against rat glioma. Anticancer Res 1997; in press.

15. Lenartz D, Stoffel B, Menzel J, and Beuth J: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 1996; 16: 3799-3802.

16. Levin VA, Silver P, Hannigan J, Wara WM, Gutin PH, Davis RL, and Wilson CB: Superiority of postradiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PVC) over BCNU for anaplastic glioma. Int J Radiat Oncol Phys Biol 1990, 18: 321-326.

17. Minckwitz von G, Dan Costa S, and Kaufmann M: Hochdosis-Chemotherapie beim Mammakarzinom. Dt Ärztebl 1997; 94: 2835-2837.

18. Riley V: Pschyoneuroendocrine influences on immunocompetence and neoplasia.

Science 1981; 212: 1100-1109.

19. Salman M: Epidemiology and factors affecting survival. In: Apuzzo MLJ (ed.) Malignant cerebral glioma. Am Assoc of Neurological Surgeons, Park Ridge, IL, USA 1990: 2835-2837.

20. Schumacher K, Beuth J, Uhlenbruck G: Prophylaxe von Lebermetastasen durch Blockade von Adhäsionsmolekülen bei kolorektalen Karzinomen. Onkologe 1997; in press.

21. Sherman CD: Cancer of the gastrointestinal tract. In: Hossfeld DK, Sherman CD, Love RR (eds.) Manual of clinical oncology, Springer Verlag, 1990: 228-252.

22. Stoffel B, Krämer K, Mayer H, and Beuth J: Immunomodulating efficacy of combined administration of galactoside-specific lectin standardized mistletoe extract and sodium selenite in BALB/c-mice. Anticancer Res 1997; 17: 1893-1896.

23. Stoffel B, Beuth J, and Pulverer G: Effect of immunomodulation with galactoside-specific mistletoe lectin on experimental listeriosis. Zbl Bakt 1996; 284: 439-442.


Ralph W. Moss, Ph.D. is director of the The Moss Reports for cancer patients. Dr. Moss is the author of eleven books and three documentaries on cancer-related topics. He is or has been an advisor on alternative cancer treatments to the National Institutes of Health, the National Cancer Institute, the American Urological Association, Columbia University, the University of Texas, the Susan G. Komen Foundation and the German Society of Oncology. He wrote the first article on alternative medicine for the Encyclopedia Britannica yearbook. He is listed in Marquis Who's Who in America, Who's Who in the World, Who's Who in the East, and Who's Who in Entertainment (as a film documentarian). This Web site does not advocate any particular treatment for cancer. We urge you to always seek competent medical advice for all health problems, especially cancer. Before consulting our site please read our full Disclaimer statement.



home - moss reports - books - - contact - order - news
members - chronicles - faq - free email newsletter