Natural Immunomodulators for the Treatment of Cancer

By Jay Udani, MD, and Myles Spar, MD, MPH

Many cancers, especially lymphomas and leukemias, may be related to a lack of normal immune system function. Persons with disorders of immunity have an increased likelihood of being diagnosed with cancer, and those with congenital immunodeficiencies develop cancers at 200 times the expected prevalence.1

The medical use and adverse effects of accepted immunomodulators (e.g., human cytokines such as interferons and interleukins) are well known: Unfortunately, they can be a cause of significant toxicity and can induce rapid development of resistance. Resistance to immunomodulatory herbs and fungi has not yet been observed, and several herbs and fungi have been shown to have immunomodulatory activity (i.e., they boost the ability of the immune system to fight cancer, primarily through improved activity of natural killer [NK] cells).

Background: The Immune System

The immune system can be separated into two divisions: specific and innate immunity. Specific immunity involves the specific identification of a foreign antigen and the organization of an attack against it by cells designed specifically for that individual target molecule. Innate immunity involves general surveillance by immune system cells designed to take out any molecules that appear foreign, even if they haven’t been specifically identified.

Both divisions are driven primarily by white blood cells. T-cells and B-cells are those white blood cells that are stimulated chiefly by specific foreign antigens, and are thus the main components of specific immunity. NK cells are types of white blood cells that are neither T-cells nor B-cells. They are the chief components of innate immunity and their role is in immune surveillance and in mediating natural resistance against tumors.

NK cells are found throughout the body and do not require a specific antigen-mediated activation. They can attack foreign or cancer cells directly without prior sensitization, unlike T-cells and B-cells, which recognize a foreign antigen through a receptor found on the antigen that specifically identifies that cell, almost like a nametag. Although most foreign cells have these receptors, many cancer cells lack such a receptor, enabling them to evade surveillance by T-cells and B-cells.

Innate Immunity and Cancer

NK cells destroy cancer cells by binding to a different, more general receptor on the cancer cell and releasing toxic granules into the cell. Cancer cells are able to defend themselves against such attack by ingesting the NK cell whole or by releasing immune-suppressive substances.2,3 There has been interest in the use of NK cells for treatment of cancers once they develop. NK cell activity—the avidity with which they recognize and bind to tumor cells—is the most important measure of their function.

Mechanisms of Action

In addition to direct cytotoxic activity against tumor cells, activated NK cells also produce a variety of cytokines, which in turn have direct anticancer cell activities and immunoregulatory effects, such as up-regulation of T-cells and B-cells and further activation of NK cells. Immunomodulators that enhance NK cell activity can stimulate production of interferon-gamma and tumor-necrosis factor-alpha.4

In human trials, NK cell activity has been shown to be depressed among patients with many different malignancies. A decrease in NK cell activity has been noted before relapse in leukemia, in breast cancer patients with regional metastases to lymph nodes, and in lymphoma.5 There is a positive correlation between NK cell activity and survival time in patients with solid tumors without metastases.6

Clinical and Laboratory Studies

Immunomodulators discussed here include astralgus, MGN-3Ô, and inositol hexaphosphate (IP6). Not all of these have been proven to be useful in cancer specifically, but all have shown some ability to improve immune function.

Astralgus

Astralgus (Astralgus membranaceus), also known as huang qi, has been used in China for more than 2,000 years. In Chinese medicine, astralgus is meant to increase the circulation of wei-chee (a protective energy) around the body. It also is used to be protect against the six primary causes of disease, the "Six Evils."7

In laboratory studies, astralgus has been shown to exert antitumor effects in murine models of renal cell carcinoma while enhancing lymphokine-activated killer cells.8

In one Chinese clinical study, astralgus and ginseng were added to traditional chemotherapy in the treatment of small cell lung cancer. The group showed improved survival rates over conventional treatment, with a gain in survival of 3-17 years.9 One Chinese study evaluated the effect of astralgus preparations in 115 cases of chemotherapy-induced leukopenia. Two concentrations of astralgus were used, 5 g and 15 g twice daily of a Chinese formulation. Both groups showed improvement in white blood cell counts with the higher concentration having a significantly stronger effect.10 Neither Chinese study has been replicated in the West.

MGN-3

MGN-3 is an arabinoxylan extracted from rice bran that is produced by hydrolyzing rice bran using enzymes from mycelia of Shiitake, Kawaratake, and Suehirotake mushrooms. It is a polysaccharide that contains (-1,4 xylopyronase hemicellulose). MGN-3 has shown improvement in NK cell activity in vitro and in vivo.

In a series of studies available only as abstracts or in abbreviated form, Ghoneum et al showed an improvement in NK activity following treatment with MGN-3 in a group of 32 cancer patients, all of whom exhibited lower than normal NK cell function at study outset.11

Ghoneum also examined the effect of MGN-3 on NK cell activity in a series of 24 individuals using 15-45 mg/kg/d for two months. NK activity was enhanced at all concentrations used and acted in a dose-dependent fashion to increase NK cell activity significantly over the duration of the study.12

Ghoneum et al also found baseline NK cell activity to be low in patients with varied advanced cancers: MGN-3 led to a significant increase in NK cell activity after 1-2 weeks and was reportedly sustained for up to five years with continued administration.13 A decrease in tumor markers and long-term stabilization of disease also were reported, though again, only through abstracted or abbreviated publication.

MGN-3 has been shown to decrease the toxicity of standard chemotherapy in animal studies. Rats receiving MGN-3 in addition to chemotherapy (doxorubicin or cisplatin) showed significant weight gain and decreased gastrointestinal pathology, and even a decreased death rate, as compared to those receiving the chemotherapy alone.14 Uyemura et al showed a direct effect of MGN-3 on tumor cell growth and cytokine production (IL-10 and IL-12) in patients with breast cancer.15 No other human studies could be identified.

Table

Abstracted data: "Natural" immunomodulators

Immunomodulator Recommended Dose Mechanism of Immunomodulation
Astralgus 1,000 mg tid of dried herb; or 9-15 g made into tea 

Activation of macrophages

IL-2 activity

Potentiation of IFN activity

MGN-3 15-45 mg/kg/d Enhanced NK cell activity
TNF-alpha induction
IP6 800 mg bid Enhanced NK cell activity

Inosital hexaphosphate (IP6)

IP6 is found in cereals and legumes, particularly in the bran of mature seeds. It is the major phosphorous storage compound of plants, comprising 1-7% of the dry weight of most cereals, nuts, and legumes.16 IP6 also is endogenous to most mammalian cells in smaller amounts.17 Cellular functions include signal transduction and cellular proliferation and differentiation.

Inositol hexaphosphate has shown anticancer activity in breast, colon, liver, and prostate cells and experimental tumors.18,19 One study by Shamsuddin showed a marked inhibition of tumor development in mice given IP6 vs. controls.20 The mechanism of action is thought to be via immunomodulation with upregulation of tumor suppressor genes. IP6 is available as a supplement in combination with inositol. Studies in humans using IP6 in cancer treatment are ongoing; however, no clinical trials in humans showing anticancer activity of IP6 have been published to date.

Adverse Effects

Astralgus may lower blood pressure or cause diuresis and potentially may cause an interaction with opiates. In Chinese medicine, astralgus usually is combined with other herbs, depending on the individual’s specific condition. Therefore, it is difficult to separate out any untoward effects from astralgus in clinical use.

In human trials using up to 45 mg/kg/d of MGN-3 for six months, there have been no reported abnormalities in blood chemistries or liver enzymes. There were no reports of side effects or interactions with other medications used.21 In animal studies, MGN-3 has shown no toxic effects in doses up to 36 g/kg. A review of the literature on MGN-3 reveals no published adverse effects.

IP6 may interfere with absorption of minerals in the stomach; therefore, it should be taken on an empty stomach. There is a concern that use of IP6 with drugs that affect platelet aggregation may increase the risk of bleeding because in vitro IP6 can inhibit platelet aggregation. This effect has not been demonstrated in humans. Because of a lack of human clinical trials, the possible adverse effects of IP6 have not been fully presented. However there have been no reports of any side effects.

Conclusion

There is an ongoing search for substances that can be used to treat cancer by utilizing the body’s own natural anticancer mechanisms. Substances that can augment innate immunity involving NK cells hold much promise.

The substances discussed here have been shown to modulate the immune system, primarily through improving NK cell activity, which is closely related to control of malignancies. Improved control helps to decrease tumor burden, which theoretically may improve local control, survival, and cancer- and treatment-related toxicity. Minimal side effects have been associated, thus far, with these substances.

Although none of these plant or fungus-based substances has been shown to be magic bullets for cancer as stand alone treatments, they all show promise as adjuncts to conventional therapy, by mitigating toxic side effects (in the case of MGN-3) and by boosting the body’s innate immunity.

The greatest weight of evidence, although largely in vitro, seems to favor the use of MGN-3 as adjunctive treatment for malignancy and the use of astralgus as immune support during chemotherapy when the patient has leukopenia.

Recommendation

Although the evidence for clinical use of the immunomodulators discussed here is still scant, there seems to be growing support for their use as an adjunct to cancer treatment. Astralgus would be beneficial in those undergoing chemotherapy who develop leukopenia. MGN-3 would be recommended as an adjunct to traditional cancer therapy, especially for those with lymphomas and leukemia, given the importance of natural killer cells in these malignancies. IP6 would not be recommended currently given the lack of clinical evidence in combination with its potential impact on coagulation.

Dr. Udani and Dr. Spar are Clinical Instructors, University of California Los Angeles School of Medicine; Dr. Udani also is Medical Director, Northridge Hospital Integrative Medicine Program, Northridge, CA.

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