In our very first BRMI e-Journal, we featured an article on GC-MAF and its therapeutic potential. In the past two years, more research has come to light as well as several excellent commercial sources of the product. This article is an update of current immunotherapy practices using GcMAF.
In review, the immune system consists of a multitude of cells and cell lines that communicate with one another through specific messenger substances.
Immunotherapy uses cells, messenger substances, and molecules to trigger a reaction in the immune system. It employs known antibodies, complement proteins, and cytokines - as well as metabolites of the vitamin D axis. Gc protein, also called vitamin D binding protein, is an abundant glycoprotein found in human blood serum as well as in other body fluids and organs.
Vitamin D Binding Protein (VDBP), also called Gc Protein
Vitamin DBP is produced in our body, mainly in the liver, especially when we are exposed to the sun. This binding protein binds to 25 (OH) vitamin D in our body for transport and storage, and plays numerous other important functions. Vitamin DBP activates macrophages through N-Acetylgalactosamine (GaINAc) - modified Gc Protein.1
Vitamin D-binding protein, the precursor protein for the macrophage-activating factor (MAF), is abundant in the serum because Gc protein circulates in remarkably high concentration (250–350 μg ml) in the bloodstream. Only 5% of Gc protein carries 25-hydroxyvitamin D3, which is a reservoir form of vitamin D. Gc protein has a strong affinity for 25-hydroxyvitamin D3, but a weak affinity for calcitriol.
Liver diseases, nephrotic syndrome, malnutrition, septic shock, and trauma is characterized by low plasma vitamin DBP concentrations, due to a diminished synthesis rate or an excessive protein loss/consumption.
The body uses vitamin D in almost three thousand genes, many of which play a crucial role in immune system function. Currently, vitamin D deficiency is a global health problem. With all the medical advances of the century, vitamin D deficiency is still epidemic. It is estimated that over a billion people worldwide are vitamin D deficient or insufficient.2 Yet no international health organization or governmental body has declared a health emergency to warn the public about the urgent need of achieving sufficient vitamin D blood levels.3
Vitamin D has important functions beyond those of calcium and bone homeostasis which include modulation of the innate and adaptive immune responses. Deficiency in vitamin D is associated with increased autoimmunity as well as an increased susceptibility to infection. Vitamin D3 deficiency can result in obesity, diabetes, hypertension, depression, fibromyalgia, chronic fatigue syndrome, osteoporosis and neuro-degenerative diseases including Alzheimer’s disease. Vitamin D deficiency may even contribute to the development of cancers, especially breast, prostate, and colon cancers. Findings also indicate that inadequate levels of vitamin D may play a role in the etiology of autism.4
Inflammation results in the hydrolysis of terminal galactose and sialic acid of the Gc protein and this is mediated by membrane-bound β-galactosidase present on activated B-cells and sialidase on T-cells to produce Gc protein-derived macrophage-activating factor (GcMAF). GcMAF has been shown to possess several biological activities, such as macrophage activation via superoxide generation5, 6, phagocytic activation7, an anti-angiogenesis effect8, 9, and antitumor activities.10, 11, 12
GcMAF activates tumoricidal macrophages against a variety of cancers. Macrophage activating factor (MAF) is a lymphokine or other receptor based signal that primes macrophages towards cytotoxicity to tumors, cytokine secretion, or clearance of pathogens. This enzymatic transformation is significantly stimulated by T and B lymphocytes and results, among other things, in a striking increase in activity levels of the macrophages.
As an essential component of the innate immune system, macrophages are phagocytic cells that multiply in response to an infection within the body. Macrophages distinguish, overwhelm, and obliterate pathogens, cancer cells, and foreign substances. These macrophages also circulate cytokines and eliminate cellular debris and cells that have undergone apoptosis. As such, macrophages act as a first-line or primary defense against intruders as they migrate to and circulate within almost every tissue, patrolling for pathogens and eliminating dead cells. They also direct other types of white blood cells, especially lymphocytes.
MAF specifically serves to activate macrophages triggering an immunomodulatory effect, by linking to the vitamin D receptor (VDR). However, to do so, the saturation of the protein needs the assistance of other nutrients such as vitamins D, A, K and organic fatty acids such as oleic acid. Organic fatty acids can be beneficial as vitamin D is a fat-based molecule and the vitamin D binding protein also binds to fatty acids to become the active form.
GcMAF is produced naturally within the gut-associated lymphoid tissue (Galt) of the small intestine. These molecules are then integrated into the body and overall function of the immune system whose primary role is to protect against illness, disease and unwanted cells within the body. Intestinal macrophages of the gastrointestinal tract, Langerhans cells, dermal macrophages, Kupffer cells, motile liver macrophages, brain microglia, alveolar and interstitial lung macrophages, spleen red pulp macrophages, and bone marrow macrophages are all examples of tissue-resident macrophages. Macrophages activated by GcMAF offer different properties that are effective against a variety of cancers in human and animal models.13, 14, 15
In recent years, immunotherapy has become an attractive new strategy not only in the treatment of cancer, but also in the treatment of many other acute and chronic diseases including autism. GcMAF-based immunotherapy has wide application for use in many diseases principally by activating macrophages to stimulate the immune system. It is only when the body can no longer produce enough GcMAF on its own, that reintroducing it externally via a bioidentical source, that it can then be considered a replacement therapy. Unlike other treatment methods, GcMAF is not about introducing a foreign substance to the body - it is simply giving the body back what it should be producing naturally to re-facilitate a healthy immune system.
According to information from the Saisei Mirai Clinics in Japan, the general goals of GcMAF and oral colostrum MAF immunotherapy are to improve well-being and quality of life, return the patient to good health so that they are able to participate in regular life-style activities, achieve long-term survival, enhance the effect of other therapies, repair the immune system, increase the number of monocytes and activate them to destroy cancer cells, viruses, bacteria and other pathogens in the body and, finally, increase the rate of maturation of dendritic cells.16, 17
Route of Administration
GcMAF therapy has been developed as an injectable and as a spray. In Japan, Europe and elsewhere, it is often administered by intravenous infusion (drip) or by IV “push”. Some doctors also administer GcMAF as an intratumoral injection together with oxidative therapy (oxygen/ozone). Another option is to use a nebulizer to deliver the protein to activate macrophages in the bronchus-associated lymphoid tissue of the lungs.
Oral forms of GcMAF are ineffective because the protein, when orally consumed, is destroyed by stomach hydrochloric acid and pancreatic protease enzymes. However, there are now some excellent oral colostrum forms that are viable in increasing bodily GcMAF. Over the past two years, reports of these products have been very positive. Colostrum-derived MAF (Cd-MAF) has multiple positive attributes, including being a safe food, easy to obtain and use, and being a non-inducer of inflammatory cytokines. Cd-MAF is becoming more commonly used as an effective macrophage activator in various immunotherapy programs.
Doctors using Cd-MAF in Europe, Japan and North America often combine this therapy with intravenous vitamin C for maximum immune effects. Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis and phagocytosis. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects.
Dosage, Frequency, and Duration
As with any immunotherapy, it is important to determine the dosage of GcMAF, the frequency of administration, and the length of time required for response to therapy before decisions about its administration can be made. There is no one-size-fits-all dosage. All dosage amounts and frequency of administration are individualized depending on the individual’s constitution and biological terrain and the condition being treated. From GcMAF’s discovery in 1990 until 2013, 0.25 ml of GcMAF each week was generally recommended. This was based on the thought that GcMAF has a half-life of 6 days. In 2013, research discovered a shorter GcMAF half-life of 3 days in certain cancers.
The Company Firstimmune by Immuno Biotech, which operates clinics in Switzerland, Germany and Guernsey, have developed protocols that greatly enhanced the effectiveness of GcMAF.18 Together with clinical feedback over several years, their recommended dosage has been re-adjusted in treatment of cancer now suggesting at least two 0.25 ml doses a week. Some individuals require 0.5 ml twice weekly to achieve results. For the treatment of an infection such as a virus they recommend administering one 0.25 - 0.5 ml injection once. Autism is sometimes treated with 0.5 ml daily, thus 5 doses per vial. Again, all protocols are individualized by the physician.
Generally, there is 2.5 ml in commercially sold vials with the contents of 1500 ng/0.5 ml., thus 7500 ng per vial.
The following is Firstimmune’s home protocol “example”:
For stage-one cancer: a standard dose of 0.25 ml GcMAF twice a week; for stage 2: three doses a week: stage 3: five doses a week; late stage 4: up to a full 1ml five times a week. No side effects should be expected with 1ml a day.
At least 10,000 IU of vitamin D3 a day, 100mcg K2, 400mg of magnesium citrate.
No sugar or carbohydrates (so no cereals or bread etc.) which feed cancer.
Consume only vegetables, fish, and white meat.
If body weight drops below your perfect weight for your height, take Branch Chain Amino Acids (BCAA) from a vitamin shop, or better, Master Amino Acid Pattern.
For nebulization the dosage is 0.5ml to 1.0 ml a day in 5ml of saline.
They recommend not to stop the GcMAF until 8 weeks after scans have been clear, or 8 weeks after nagalase levels drop below 0.65.
Gc-MAF can be safely used with a wide variety of drugs and other treatments. It may be combined with sonodynamic therapy, photodynamic therapy or both (sonophotodynamic therapy), various medicinal mushroom extracts, hyperthermia, high-dose IV Vitamin C, low dose naltrexone, alpha-lipoic acid, oxidative therapies and other immunotherapies – such as mistletoe and thymus peptides.
It is recommended that minimal use of steroids is desirable because of their immune suppressing effect. However, steroids may be used with GcMAF if necessary, but do compromise the efficacy of the immunotherapy. With conventional oncology, radiation therapy is less detrimental immunologically than cytotoxic chemotherapy. Bear in mind, cytotoxic chemotherapy can make white cell counts so low that GcMAF treatment is totally ineffective.
Saisei Mirai clinics in Japan inject their GcMAF product intramuscularly at 1500 ng/0.5 ml, 2-3 times per week in the treatment of cancer and other conditions. Together with this immunotherapy, they also incorporate an integrative approach to treating cancer and other illnesses. They further recommend that more frequent dosing (daily or every second day) may be safely used with more advanced stage of disease, or initially in the treatment course. In certain cases, as in many other clinics, Saisei Mirai doctors administer their GcMAF by intravenous injection, 0.5-1.0 ml 2-3 times per week in 20 ml or more saline.
Moreover, the frequency of administration also depends upon the individual responsiveness associated with any vitamin D receptor (VDR) polymorphism. The association between polymorphisms of gene coding for VDR should always be considered. Additionally, blood levels of 25-hydroxyvitamin D should be periodically monitored. Insufficient vitamin D is linked to virtually every age-related disorder including cancer, vascular disease, and chronic inflammation. Generally, many doctors consider the ideal ranges for 25-hydroxyvitamin D to be between 50-80 ng/mL. For some individuals, to maintain that ideal level, it may be necessary to take vitamin D3 doses of up to 5,000 IU to 10,000 IU daily.
Injectable GcMAF, sprays and oral forms of colostrum-derived MAF are not used as stand-alone therapies. Instead, in the world of bioregulatory medicine, this form of immunotherapy is used in concert with a comprehensive, multi-therapeutic modality approach. This involves incorporating individualized dietary approaches, nutritional supplementation, organ and extracellular matrix detoxification, improvement of acid-base balance, as well as all-important psycho-emotional supportive therapies. In relationship to cancer patients, it is important to know which patients and which types of cancers are the best candidates for GcMAF therapy. Prostate, breast, colon, liver, stomach, lung (including mesothelioma), kidney, bladder, uterus, ovarian, head/neck and brain cancers, fibrosarcomas and melanomas are the types of cancer tested thus far.19 Although many types of cancer have been the focus for GcMAF therapy, it has not been used as a clinical treatment for lung and brain cancer.
The duration of GcMAF therapy depends on the individual’s condition. Usually, with most cancer patients or those with chronic viral infections, 4 to 6 months is necessary to fully activate the immunity. Maintenance is often continued with oral colostrum MAF, together with vitamin D3, oleic acid supplementation, and intravenous vitamin C. Monitoring GcMAF Treatment and Labs
GcMAF administration must always be monitored by a physician trained in its use. Aside from the usual cancer tests (monitoring the effectiveness of treatments), there are two additional tests that are often used. The first is the monocyte count of a white blood cell differential. GcMAF therapy increases the number of monocytes as it activates macrophages. A patient’s monocyte count will generally rise in the early stages of GcMAF treatment and indicates a response to GcMAF. Normal monocyte levels are between 2% and 10% of the total differential. Upward of 6% or more is considered an optimum response to GcMAF treatment.
The second test is nagalase levels. Cancers and viruses both make the enzyme α-N-acetylgalactosaminidase (nagalase) and increased serum levels of nagalase have been reported in many cancer patients. Thus, nagalase in blood is a sensitive test for monitoring the efficacy of therapy in cancer and certain viral infections, including HIV and recently HSV-1/2. Because of the short half-life of nagalase, the method is suitable for monitoring various types of therapy. The great sensitivity of the test may help the physician/oncologist in obtaining a better understanding of the therapy and to fine-tune the treatment.
It has been suggested that the nargalase enzyme is responsible for the inactivation, or specifically deglycosylation of GcMAF.20, 21, 22 By complete deglycosylation, Gc-protein can no longer be converted to MAF. Since macrophage activation for phagocytosis and antigen presentation is the first step in the immune cascade, loss of precursor activity via increased nagalase leads to immune suppression. Even though the intracellular (lysosomal) form of nagalase is vital for proper hepatic cell function, the extracellular form (secreted by cancer cells) seems only to benefit the progression of cancer.23
Specialized laboratories can now measure the level of nagalase in the blood.24 An elevated nagalase test result reveals that either cancer or a virus (or both) could be present. It has been established that nagalase activity is directly proportional to viable tumor burden, whereas decreased nagalase activity is associated with improved clinical conditions. Hence, some doctors using GcMAF employ nagalase testing to determine the efficacy of the therapy.
According to current articles and research centers, the recommended reference range of nagalase in the serum of healthy people is between 0.32 and 0.95 nM/min/mg of substrate, although in some articles the normal range is slightly lower (up to 0.65nM/min/mg).25 Be advised that reference ranges differ slightly depending on the laboratory.
Nagalase activity is directly proportional to viable tumor burden. Studies correlating nagalase levels with tumor burden suggest that the measurement of this enzyme can diagnose the presence of cancerous lesions below levels detectable by other diagnostic means. Still, additional research is warranted to ascertain a universal and reliable normal threshold. Because the measurement of this enzyme can diagnose the presence of cancerous lesions below levels detectable by other diagnostic means, nagalase testing may eventually become a standard biomarker for early cancer detection.
GcMAF Side Effects
GcMAF has shown no side effects of its own. The primary reason being that its molecular structure is bioidentical (identical to the GcMAF made by the body). So long as the GcMAF is pure, there is no reason to expect any side effects.
However, as the immune system is strengthened there may be minor secondary side effects due to pathogenic organisms dying off – such as viruses, bacteria, yeast, etc. In a die-off reaction, also called a Herxheimer reaction, there is a release of endotoxins, proteins, and oxidizing agents that results in an increase in inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6, and interleukin-8. The symptoms of a die-off reaction can potentially temporarily worsen underlying symptoms.
A pure GcMAF protein contains only molecules of a single protein (no other molecules of any kind). Impurities cause compromised effectiveness, adverse reactions, and symptoms of toxicity. Beware because there are “bootleg” or phony versions of GcMAF being manufactured that are impure, contaminated, and consequently potentially toxic. These products are often sold over the internet, and their packaging may look identical to the real product. As more GcMAF manufacturing companies and products enter into the market, many products are nothing more than peptides containing zero GcMAF. This of course, will eventually give GcMAF a bad name as “noneffective”.
It is best to purchase GcMAF directly from the clinics in Europe or Japan - such as Saisei Mirai in Japan who has led the way for several years. These clinics usually require the patient to undergo GcMAF treatment at the clinic, and then dismiss the patient with enough injectable product or oral colostrum MAF product to follow up at home. Also, quality GcMAF may be purchased through Healing Oracle website.26
The Future of GcMAF
The topic of GcMAF therapy is still highly controversial. And yet, it is estimated that more than 300 doctors in 80 countries are now using injectable GcMAF, sprays, and oral CdMAF. Generally, news stories about GcMAF are not published by newspapers or TV but circulated via the Internet. The laboratory and clinical study of cancer immunotherapy is rapidly advancing, but unfortunately, current research of GcMAF is limited to Japan and selective parts of Europe. Several large pharmaceutical companies and their partner regulatory agencies have done much to discredit - and make unavailable - the product. The internet is full of quackery websites discrediting GcMAF and the doctors who advocate its use. It is tragic that this harmless body protein, studied for over 25 years as a promising immunotherapy agent, is not given more consideration for further research in the U.S.
The efficacy and safety of this product has continued to be endorsed in numerous studies. Because GcMAF is produced by the human body, it is non-toxic (provided the manufacturing process is pure). At present, it appears non-scientific reasons are preventing FDA approval. With so many lives at risk and no real cures at hand, the FDA should allow expanded access or “compassionate use” for GcMAF therapy to proceed with the requirement of real-time adverse event reporting to ensure patient safety.
Join Amanda Mary Jewell and Healing Oracle Group on Facebook and visit the Healing Oracle website.
References 1. Delanghe JR, Speeckaert R, Speeckaert MM. Behind the scenes of vitamin D binding protein: more than vitamin D binding. Best Pract Res Clin Endocrinol Metab 2015;29(5): 773-786.
2. Holick, Michael F., and Tai C. Chen. Vitamin D deficiency: a worldwide problem with health consequences. The American journal of clinical nutrition 87, no. 4 (2008): 1080S-1086S.
3. Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol 2014; 5: 151.
4. El-Ansary, Afaf, John J. Cannell, Geir Bjørklund, Ramesa Shafi Bhat, Abeer M. Al Dbass, Hanan A. Alfawaz, Salvatore Chirumbolo, and Laila Al-Ayadhi. In the search for reliable biomarkers for the early diagnosis of autism spectrum disorder: the role of vitamin D. Metabolic brain disease 33, no. 3 (2018): 917-931.
5. Yamamoto, Nobuto, Dwight D. Lindsay, Venkateswara R. Naraparaju, Ruth Ann Ireland, and Steven N. Popoff. A defect in the inflammation-primed macrophage-activation cascade in osteopetrotic rats. The Journal of Immunology 152, no. 10 (1994): 5100-5107.
6. Mohamad SB, Nagasawa HI, Uto YO, Hori HI. Preparation of Gc protein-derived macrophage activating factor (GcMAF) and its structural characterization and biological activities. Anticancer Research. 2002;22(6):4297-300.
7. Nagasawa, Hideko, Hideyuki Sasaki, Yoshiihiro Uto, Shinichi Kubo, and Hitoshi Hori. Association of the macrophage activating factor (MAF) precursor activity with polymorphism in vitamin D-binding protein. Anticancer research 24, no. 5C (2004): 3361-3366.
8. Kanda, Shigeru, Yasushi Mochizuki, Yasuyoshi Miyata, Hiroshi Kanetake, and Nobuto Yamamoto. Effects of vitamin D3-binding protein-derived macrophage activating factor (GcMAF) on angiogenesis. Journal of the National Cancer Institute 94, no. 17 (2002): 1311-1319.
9. Kisker, Oliver, Shinya Onizuka, Christian M. Becker, Michael Fannon, Evelyn Flynn, Robert D'Amato, Bruce Zetter et al. Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice. Neoplasia 5, no. 1 (2003): 32-40.
10. Nonaka, Koichi, Shinya Onizuka, Hiromi Ishibashi, Yoshihiro Uto, Hitoshi Hori, Toshiyuki Nakayama, Nariaki Matsuura, Takashi Kanematsu, and Hikaru Fujioka. Vitamin D binding protein-macrophage activating factor inhibits HCC in SCID mice. Journal of Surgical Research 172, no. 1 (2012): 116-122.
11. Kanda, Shigeru, Yasushi Mochizuki, Yasuyoshi Miyata, Hiroshi Kanetake, and Nobuto Yamamoto. Effects of vitamin D3-binding protein-derived macrophage activating factor (GcMAF) on angiogenesis. Journal of the National Cancer Institute 94, no. 17 (2002): 1311-1319.
12. Mohamad SB, Nagasawa H, Sasaki HI, Uto Y, Nakagawa YO, Kawashima K, Hori H. Gc protein-derived macrophage activating factor (GcMAF): isoelectric focusing pattern and tumoricidal activity. Anticancer research. 2003;23(6):4451-8.
13. Mohamad SB, Nagasawa H, Uto Y, Hori H. Preparation of Gc protein-derived macrophage activating factor (GcMAF) and its structural characterization and biological activities. Anticancer Res. 2002; 22:4297–300.
14. Pacini S, Punzi T, Morucci G, Gulisano M, Ruggiero M. Effects of vitamin D-binding protein-derived macrophage-activating factor on human breast cancer cells. Anticancer Res. 2012; 32:45–52.
15 Homma S, Yamamoto N. Activation process of macrophages after in vitro treatment of mouse lymphocytes with dodecylglycerol. Clin Exp Immunol. 1990; 79:307–13.
17. Inui, Toshio, Kaori Makita, Hirona Miura, Akiko Matsuda, Daisuke Kuchiike, Kentaro Kubo, Martin Mette et al. Case report: A breast cancer patient treated with GcMAF, sonodynamic therapy and hormone therapy. Anticancer research 34, no. 8 (2014): 4589-4593.
19. Thyer L, Ward E, Smith R, et al. GC protein-derived macrophage-activating factor decreases alpha--acetylgalactosaminidase levels in advanced cancer patients. Oncoimmunology 2013; 2:e25769.
20. Yamamoto N, Naraparaju VR, Moore M, Brent LH. Deglycosylation of serum vitamin D3-binding protein by alpha-N-acetylgalactosaminidase detected in the plasma of patients with systemic lupus erythematosus. Clin Immunol Immunopathol 1997;82:290-8.
21. Reddi AL, Sankaranarayanan K, Arulraj HS, Devaraj N, Devaraj H. Serum alpha-N-acetylgalactosaminidase is associated with diagnosis/prognosis of patients with squamous cell carcinoma of the uterine cervix. Cancer Lett 2000;158:61-4.
22. Korbelik M, Naraparaju VR, Yamamoto N. The value of serum alpha-N-acetylgalactosaminidase measurement for the assessment of tumour response to radio- and photodynamic therapy. Br J Cancer 1998; 77:1009-14.
23. Mohamad SB, Nagasawa H, Uto Y, Hori H. Tumor cell alpha-N-acetylgalactosaminidase activity and its involvement in GcMAF-related macrophage activation. Comp Biochem Physiol A Mol Integr Physiol 2002; 132:1-8.
24. Health Diagnostics and Research Institute (HDRI), formerly Vitamin Diagnostics, is a CAP-accredited, CLIA-registered, and New Jersey-licensed diagnostic and research laboratory offering an extensive repertoire of specialty analyses to serve the mainstream, alternative, and preventive medical community - http://www.hdri-usa.com/
25. Saburi, Ehsan, et al. Is α-N-acetylgalactosaminidase the key to curing cancer? A mini-review and hypothesis. Journal of BU ON.: official journal of the Balkan Union of Oncology 22.6 (2017): 1372.
The information in this monograph is intended for informational purposes only, and does not constitute medical advice. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Its aim is to help readers better understand current topics related to immunotherapy. Information is based on review of scientific research data, historical practice patterns, and clinical experience. Users should always consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.