Cancer Imunoterapi

Abstract
 Mushroom polysaccharides derived from medicinal mushrooms are well established to have immune-modulating and anti-tumor properties.  However, with a molecular weight of up to 300,000 Daltons, they are too large to be absorbed efficiently by the human body.  MRT ELFAHEX is a proprietary cultured mushroom extract containing lower-molecular weight and more absorbable acylated alpha-glucans.  This unique mushroom extract has been shown to be a natural biological response modifier (BRM) for use in cancer immunotherapy. In this review, we summarize and discuss previously published clinical research on this alpha-glucan rich mushroom extract as a biological response modifier in cancer patients.  Proposed mechanisms of action are also examined.
Introduction
 Cancer immunotherapy is a promising approach for integrative cancer therapy. During immunotherapy, patients are given biological response modifiers (BRM), substances that enhance the innate defensive powers of the immune system.  The use of BRMs has become an important therapeutic option for treating many types of cancer and can be utilized alone or as adjuvant therapy to other cancer treatments such as chemotherapy.
In Asia, mushrooms have been valued for their medicinal properties for over five millennia. Of particular interest are mushrooms that belong to the class of basidiomycetes, whose active constituents are polysaccharide compounds.  Mushroom polysaccharides have been extensively studied for their ability to enhance host immunity and have been shown to be effective as biological response modifiers (BRM) in cancer immunotherapy. The mechanisms of action include natural killer cells enhancement, up-regulation of cytokines, anti-inflammatory properties and anti-tumor activity.[1]^{,[2],[3],[4],[5]}
Glucans are a subcategory of polysaccharides.  While only approximately 300 glucan polymers are found in nature, they are quite a diverse group of compounds. Glucans are high-molecular weight compounds, ranging from 50,000 up to 300,000 Daltons, and are often too large to be efficiently absorbed in the GI tract.  They also vary in their chemical composition (type of sugar) and spatial configuration (α or β linkage, degree of branching, tertiary conformation), all of which may have an effect on their bioavailability and biological activity. While oral administration of polysaccharides has a known effect on intestinal mucosal immunity, many glucans that have been shown to have in vitro or systemic immunomodulating activity in animals via intravenous, intraperitoneal, subcutaneous, or intramuscular routes, may not be as effective when taken orally due to low bioavailability in the GI tract. ^5,[6],[7]
In an effort to enhance absorption of the biologically-active polysaccharides and glucans, a patented fermentation process[8] has been developed using a hybridization of several types of Basidomycota mushroom mycelia. The mycelia are cultivated under laboratory conditions in a liquid medium, rather than in the soil or wood growth medium that is natural to these fungi. Following harvest, the mycelia undergo a fermentation process using enzymes naturally present in the cells to break the large polysaccharides down to a more bioactive size and then they are extracted from the cells.  This proprietary extract, called MRT ELFAHEX, contains mostly oligosaccharides, of which major portions are acetylated α 1- 4 glucan structures with low-molecular weight. At only 5000 daltons, these unique α-glucans are more easily absorbed in the gut than high molecular weight of β-glucans. This α-glucan rich mushroom extract is widely used in Japan and China to as a dietary supplement and functional food to boost immune function in healthy individuals and as a BRM for cancer patients undergoing chemotherapy and radiation. This unique mushroom extract has also been shown in a Phase 1 trial to be well tolerated and largely free of adverse effects.[9]
Clinical Evidence
The use of BRM for treatment of cancer patients has resulted in considerable success over the past few decades.  The National Cancer Institute defines BRM as “agents or approaches that modify the relationship between tumor and host by modifying the host’s biological response to tumor cells with resultant therapeutic effects.”[10] In addition, BRM may be used alone or as adjuvants to cancer chemotherapeutic agents to counteract immunosuppression and subsequent negative side effects resulting from chemotherapy, or to improve immune function so that patients can tolerate further treatment.[11]
First line chemotherapy treatments for patients are usually accompanied by significant toxicity and side effects, including bone marrow suppression and subsequent neutropenia. Hangai et al. completed a retrospective study in breast cancer patients and found that in patents taking 1 g of MRT ELFAHEX after each meal during their chemotherapy treatment, the severity of neutropenia was reduced compared to the control group.  In addition, patients required lower dosage of G-CSF (granulocyte colony-stimulating factor) during weekly chemotherapy treatment, indicating an increase in neutrophil count during bone marrow suppression and the potential to increase the intensity of chemotherapy to achieve a better clinical outcome.[12]
Several studies have shown that MRT ELFAHEX can be utilized as a BRM to improve prognosis, survival rate and quality of life in cancer patients. In a prospective cohort study with postoperative hepatocellular carcinoma patients, MRT ELFAHEX was found to improve prognosis following resection of a liver tumor. MRT ELFAHEX (3 grams/day) was administered to 113 of 269 patients after surgery.  The treatment group had a significantly longer no-recurrence period and an overall increased survival rate when compared to the control.[13] Cowawintaweewat et al. investigated administering 6 grams of MRT ELFAHEX as a BRM on advanced liver patients, whom often have no other treatment option.  The preliminary results from 23 patients showed that all 10 (100%) patients in the control group died within 3.5 months whereas 8 (61.5%) patients in the MRT ELFAHEX group were still alive after that period. Follow-up of 6 of the MRT ELFAHEX-treated patients reported a survival time of more than 7 months (two times the median average), with one patient surviving more than 24 months. In addition, MRT ELFAHEX delayed the gradual decline of the physiological status as measured by quality of life (QOL). These results were so significant that it seemed unethical to randomize more patients into the control group, so all newly enrolled patients in this institution are treated with MRT ELFAHEX.[14]
Ito et al. investigated the safety and efficacy of 3 grams/day MRT ELFAHEX on chemotherapy-induced adverse effects and QOL in patients with a variety of different cancers (pancreatic, ovarian, lung, and colorectal cancer) in different clinical stages (I-IV).   Twenty-four patients were treated with chemotherapy for one cycle without supplementation and then received their second cycle with MRT ELFAHEX. Adverse effects and QOL were monitored, as well as DNA levels of herpes virus type 6 (HHV-6) in saliva as a biomarker for fatigue. The DNA levels of HHV-6 were significantly increased after the first cycle of chemotherapy, but significantly decreased during chemotherapy in conjunction with MRT ELFAHEX.  MRT ELFAHEX also improved QOL scores and hematotoxicity and hepatotoxicity.[15]
The effect of MRT ELFAHEX on tumor regression, reduction of chemotherapy side effects and quality of life was also evaluated in patients with advanced head and neck cancers such as cancer of the tongue and cheek, and oro-pharyngeal and naso-pharynx cancer. Patients were administered 3 grams of MRT ELFAHEX every day prior to chemotherapy and for one week post-therapy.  A significant reduction in side effects were reported including improved strength, better appetite, and reduction of side effects like nausea, vomiting and GI disturbances as compared to their previous chemotherapy treatments.  In addition, tumors regressed in approximately half of the patients.[16]
Kawaguchi conducted a prospective cohort study to evaluate MRT ELFAHEX as a BRM in patients with gastric or colon cancer.   Patients received 3-6 grams/day of MRT ELFAHEX as a post-operative adjunctive therapy in conjunction with standard chemotherapy.  The combination of chemotherapy and MRT ELFAHEX significantly improved the cumulative 5-year survival rates of Stage IA to Stage IIIA gastric cancer patients and Stage II to Stage III colon cancer patients.[17]
Mechanisms of Action
 A large number of studies have been completed in an attempt to elucidate the mechanism in which MRT ELFAHEX exerts its effect on the immune system.  It appears that it increases both the activity the innate immune response and the adaptive immune response.
A component of the innate immune system, natural killer (NK) cells are cytotoxic lymphocytes that survey their environment for malignant, virus-infected and haematopoietic allogeneic cells without prior immunization, such as tumor cells or virus-infected cells.[18]  There is accumulating evidence that NK cells are crucial for the defense against tumors via this immunosurveillance activity.[19]^,[20] In fact, low NK cell activity appears to be associated with increased cancer risk.[21] The transplantation of NK killer cells has shown promise as a form of immunotherapy in cancer patients, but it is not without side effects.[22] In animal models, MRT ELFAHEX has been shown to enhanced NK cell activity,[23]^,[24],[25] indicating that it could be an alternative oral option for improving activity of NK cells.  Studies in cancer patients provide further evidence. In a study with cancer patients with reduced NK cell activity compared to normal control, 4 months of MRT ELFAHEX administration (6 grams/day) resulted in an increase in NK cell activity back to normal levels.[26] Won also reported increased NK cell activity after MRT ELFAHEX intake in cancer patients as measured by an increase in the ratio of NK cells to total lymophocytes.[27] In a non-randomized open-label trial, a 249% increase in NK cell activity was observed in cancer patients following MRT ELFAHEX administration over a16-week period.[28]
Another element of the innate immune response are dendritic cells, a type of antigen-presenting cell found in tissues that are in contact with the external environment, such as the skin, lungs, and epithelial lining.  Dendritic cells naturally produce the protective cytokine IL-12, which mobilizes innate NK cells and is also involved in priming adaptive immune cells, specifically tumor-specific T cells. This dual action of the dendritic cells links innate immunity to adaptive immunity[29] and therefore has the potential to improve antitumor immune responses. Clinical research has also shown that MRT ELFAHEX increases the number of dendritic cells. In a double-blind, placebo-controlled trial, administration of MRT ELFAHEX in healthy individuals resulted in a significantly higher number of total dendritic cells compared to that at baseline and values from control subjects.[30]
Lastly, MRT ELFAHEX has also been shown to increase T-cell activity in vitro,^25,[31] and in mice,[32] which may enhance the overall immune system of immunosuppressed cancer patients.
 Summary
 In conclusion, MRT ELFAHEX is a unique enzyme-modified mushroom mycelia extract rich in α-glucans shown to have clinical potential as a biological response modifier in cancer immunotherapy treatment. Clinical evidence supports its use as an adjuvant in combination with chemotherapy where it may have a direct effect on tumor regression as well as reduce such side effects such as bone marrow suppression, fatigue and reduced quality of life.  In advanced cancer patients, its administration resulted in improved prognosis and survival rate. The mechanism of action for these results appears to be its proven ability to increase NK cell activity, thereby improving tumor immunosurveillance, as well as enhance the innate immune response of cancer patients, especially those who are immunosuppressed as a result of chemotherapy treatment. MRT ELFAHEX may also have an effect on dendritic cells, linking the innate and adaptive immune response, coordinating a comprehensive immune response to cancer.

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