by Jeffrey Dach MD
This article is part two of a series
Left Image Breast Cancer (red arrow) on PET and CAT scans Courtesy of Wikimedia Commons
In part one of this series, we discussed a mouse with innate immunity to cancer by virtue of its immune cells which kill the cancer cells as if they were any other microbial invader. In this article, part two, we will expand on this idea by exploring the work of Dr. Yamamoto who discovered the Macrophage Activating Factor (GcMAF) in 1990 at the Socrates Institute in Philadelphia. (4) Since then, Dr. Yamamoto has published three human clinical trials showing remarkable results for breast(5), colo-rectal (10) and prostate cancer(11).
What is MAF – Macrophage Activating Factor?
MAF is a protein which activates our macrophages, the microscopic white cells that kill invading microbes and cancer cells. MAF is made from a precursor protein called the Gc protein.
In a way, cancer cells are clever little devils because they disable our immune system, in order to enhance their own survival. Dr. Yamamoto discovered that cancer cells do this by secreting an enzyme called Nagalase which prevents the precursor protein Gc from being converted to MAF. This Nagalase enzyme activity can actually be measured in cancer patients, and greater tumor burden corresponds with higher Nagalase enzyme activity (as one would expect). Elimination of the tumor results in reduction of Nagalase activity to lower, more normal values.. (5)
Left Image: CAT SCan Brain Showing enhancing metastatic lesions from breast cancer primary. Courtesy of wikimedia commons.
Dr. Yamamoto devised a technique for restoring Gc protein activity which creates the most potent macrophage activating factor ever discovered, having no adverse effects. He called it GcMAF. Macrophages treated in vitro with GcMAF (100 pg/ml) are highly effective at killing breast cancer cells.
GcMAF for Metastatic Breast Cancer-Human Trial
Dr. Yamamoto then studied his GcMAF in human metastatic breast cancer patients with weekly injections of 100 ng of GcMAF .(5) Dr. Yamamoto found that over time, as treatment with GcMAF progresses, the MAF precursor activity of patient Gc protein increased, and the serum Nagalase decreased.(5). After 5 months of weekly GcMAF injections , the cancer patients elevated Nagalase activity had returned to normal levels, same as healthy controls. Over the next four years, these sixteen treated metastatic Breast Cancer patients remained cancer free with no recurrence.(5) In 2008, Dr Yamamoto published his landmark study on human breast cancer.(5)
Left Image Red Arrow points to Colon Cancer with Apple Core Lesion on Barium Enema Xray courtesy of Radiopedia.org.
In 2008, Yamamoto published his study on 8 patients with metastatic colorectal cancer . They all had significant metastatic disease after primary resection.(10) Nagalase activity fell to normal levels with GcMAF injections, and remained low with no cancer recurrence over 7 years of observation. This was supported by serial CAT scans that remained negative.
Left image: Prostate Cancer Bone Mets (Red Arrow)courtesy of Radiopedia.org
Dr. Yamamoto studied GcMAF in 16 patients with metastatic prostate cancer with excellent results, Nagalase activity declined to normal, and there was no evidence of tumor recurrence over 7 years of observation. (10)
“Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF. As the MAF precursor activity increased, their serum Nagalase activity decreased. Because serum Nagalase activity is proportional to tumor burden, the entire time course analysis for GcMAF therapy was monitored by measuring the serum Nagalase activity. After 14 to 25 weekly administrations of GcMAF (100 ng/week), all 16 patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor-free. No recurrence occurred for 7 years.”quote from abstract of 2008 paper(10)
The Saisei Mirai Clinic in Kobe Japan
Left Image: Dr Toshio Inui, MD.established Saisei Mirai Clinic in Kobe In 2010.
Toshio Inui, MD of the Saisei Mirai Clinic in Kobe Japan has treated over 345 patients with GcMAF combined with other modalities, and reports his results in Anticancer Research July 2013 (2,3)
At the Saisei Mirai clinic, Dr. Inui treats cancer patients with GcMAF immunotherapy in combination with other related therapies, such intravenous vitamin C, alpha lipoic acid, hyperthermia, and LDN (low dose naltrexone)
Dr Inui says his results are mixed, and describes his treatment as “hopeful” He presents three cases in which treatment was remarkably effective:
Quoted from Anticancer Research.(3)
Patient 1. A 71-year-old man was diagnosed with thymic carcinoma with lung metastasis. The patient received 24 weeks of the integrative immunotherapy. No progression of the cancer was found 12 months after completion of the therapy.
Patient 2. A 74-year-old man was diagnosed with prostate cancer with multiple bone metastases. He received 12 weeks of the integrative immunotherapy combined with hyperthermia therapy. Bone scintigram results nine months after initiation of the therapy were normal and metastatic tumors had disappeared.
Patient 3. A 72-year-old woman was diagnosed with metastatic liver cancer after sigmoidectomy and bilateral oophorectomy. She received 24 weeks of the integrative immunotherapy combined with 55 Gy of radiation. There was no evidence of local recurrence or metastatic disease on Positron Emission Tomography (PET) and Computed Tomography (CT) scans 12 months after initiation of the therapy.
Conclusion: The information is now overwhelming that cancer immunotherapy with GcMAF is highly effective with no adverse effects. The National Institute of Health (NIH) has wasted billions on ineffective treatments in the “War Against Cancer” started by Nixon. in the 1970’s. I propose allocating a billion dollars of NIH funding for research on GcMAF immunotherapy. Do you think this would win the war and give us a CURE FOR CANCER? You Betcha.
Articles with Related Interest:The GcMAF Book by Tim Smith MD
Update 2015: Articles Retracted
Yamamoto, Nobuto, et al. “Retracted: Immunotherapy of metastatic breast cancer patients with vitamin D‐binding protein‐derived macrophage activating factor (GcMAF).” International Journal of Cancer 122.2 (2008): 461-467.
Yamamoto, Nobuto, et al. “RETRACTED ARTICLE: Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF.” Cancer Immunology, Immunotherapy 57.7 (2008): 1007-1016.
Yamamoto, Nobuto, Naofumi Ushijima, and Yoshihiko Koga. “Retracted: Immunotherapy of HIV‐infected patients with Gc protein‐derived macrophage activating factor (GcMAF).” Journal of medical virology 81.1 (2009): 16-26.
News update June/July 2015
Articles with related Interest:
Jeffrey Dach MD
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This article is part two of a series, For Part One, Click Here
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Links and References
Dr Toshio Inui, MD., Graduated from Kyoto Prefectural University of Medicine in 1978. At the age of 33, after gaining experience working in the internal medicine department at a general hospital as a physician, he established Inui Clinic for the treatment of internal diseases. He soon came to develop a reputation for careful and heartwarming medical examinations which made him popular with patients.
After the loss of his father due to cancer, he came to realize the limitations of conventional therapies for cancer such as surgery, chemothearapy anticancer drugs and radiation therapy, and he started his new practice specializing in immunotherapy for cancer. He also changed his clinic name to Inui Immunotherapy Cancer Clinic.
In 2010 he established Saisei Mirai Clinic in Kobe pdf file:
2) nGcMAF: our next generation immunotherapy in nature-outlook-saisei-mirai
by Uto, Yoshihiro, Hitoshi Hori, Kentaro Kubo, Masamitsu Ichihashi, Norihiro Sakamoto, Martin Mette, Toshio Inui, and Trade Center. Nature 485 (2012): S67-S70.
2013 By March 2013, Saisei Mirai have treated over 345 patients with GcMAF
Anticancer Res. 2013 Jul;33(7):2917-9.
Clinical Experience of Integrative Cancer Immunotherapy with GcMAF.
Inui T, Kuchiike D, Kubo K, Mette M, Uto Y, Hori H, Sakamoto N.
Division of Food and Drug Evaluation Science, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017,
Japan.Immunotherapy has become an attractive new strategy in the treatment of cancer. The laboratory and clinical study of cancer immunotherapy is rapidly advancing. However, in the clinical setting, the results of cancer immunotherapy are mixed. We therefore contend that cancer immunotherapy should be customized to each patient individually based on their immune status and propose an integrative immunotherapy approach with second-generation group-specific component macrophage activating factor (GcMAF)-containing human serum.
PATIENTS AND METHODS:The standard protocol of our integrative cancer immunotherapy is as follows: i) 0.5 ml GcMAF-containing human serum is administered intramuscularly or subcutaneously once or twice per week for the duration of cancer therapy until all cancer cells are eradicated; ii) hyper T/natural killer (NK) cell therapy is given once per week for six weeks; iii) high-dose vitamin C is administered intravenously twice per week; iv) alpha lipoic acid (600 mg) is administered orally daily; v) vitamin D3 (5,000-10,000 IU) is administered orally daily.
RESULTS:By March 2013, Saisei Mirai have treated over 345 patients with GcMAF. Among them we here present the cases of three patients for whom our integrative immunotherapy was remarkably effective.
CONCLUSION:The results of our integrative immunotherapy seem hopeful. We also plan to conduct a comparative clinical study.
4) Second GcMAF Immunology Conference 2013 Sponsored by Immuno Biotech
It is our immune system that prevents and destroys disease
The first research was done in 1990 by Dr Yamamoto in Philadelphia; and since then 59 research papers have been published by 142 scientists proving that GcMAF is a vital part of the immune system. Chronic diseases succeed by preventing production of your own GcMAF, which collapses your immune system. When administered externally, GcMAF rebuilds the immune system, and the immune system then eradicates early stage cancer and other diseases.
2008 metastatic breast cancer patients Yamamoto
Int J Cancer. 2008 Jan 15;122(2):461-7.
Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF).by Yamamoto N, Suyama H, Yamamoto N, Ushijima N. Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA 19126-3305, USA.
Serum vitamin D3-binding protein (Gc protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of breast cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-
Efficacy of GcMAF for treatment of metastatic breast cancer was investigated with 16 nonanemic patients who received weekly administration of GcMAF (100 ng). As GcMAF therapy progresses, the MAF precursor activity of patient Gc protein increased with a concomitant decrease in serum Nagalase.
Because of proportionality of serum Nagalase activity to tumor burden, the time course progress of GcMAF therapy was assessed by serum Nagalase activity as a prognostic index. These patients had the initial Nagalase activities ranging from 2.32 to 6.28 nmole/min/mg protein. After about 16-22 administrations (approximately 3.5-5 months) of GcMAF, these patients had insignificantly low serum enzyme levels equivalent to healthy control enzyme levels, ranging from 0.38 to 0.63 nmole/min/mg protein, indicating eradication of the tumors. This therapeutic procedure resulted in no recurrence for more than 4 years.
2012 Italy human breast cancer cells.
Anticancer Res. 2012 Jan;32(1):45-52.
Effects of vitamin D-binding protein-derived macrophage-activating factor on human breast cancer cells. Pacini S, Punzi T, Morucci G, Gulisano M, Ruggiero M.
Department of Anatomy, Histology and Forensic Medicine, Viale Morgagni 85, University of Firenze, Italy.
Searching for additional therapeutic tools to fight breast cancer, we investigated the effects of vitamin D-binding protein-derived macrophage activating factor (DBP-MAF, also known as GcMAF) on a human breast cancer cell line (MCF-7).
MATERIALS AND METHODS:The effects of DBP-MAF on proliferation, morphology, vimentin expression and angiogenesis were studied by cell proliferation assay, phase-contrast microscopy, immunohistochemistry and western blotting, and chorioallantoic membrane (CAM) assay.
RESULTS:DBP-MAF inhibited human breast cancer cell proliferation and cancer cell-stimulated angiogenesis. MCF-7 cells treated with DBP-MAF predominantly grew in monolayer and appeared to be well adherent to each other and to the well surface. Exposure to DBP-MAF significantly reduced vimentin expression, indicating a reversal of the epithelial/mesenchymal transition, a hallmark of human breast cancer progression.
CONCLUSION:These results are consistent with the hypothesis that the known anticancer efficacy of DBP-MAF can be ascribed to different biological properties of the molecule that include inhibition of tumour-induced angiogenesis and direct inhibition of cancer cell proliferation, migration and metastatic potential.
2013 MAF itself inhibits prostate cancer cells in absence of MAcrophages
PLoS One. 2010 Oct 18;5(10):e13428. doi: 10.1371/journal.pone.0013428.
Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells.by Gregory KJ, Zhao B, Bielenberg DR, Dridi S, Wu J, Jiang W, Huang B, Pirie-Shepherd S, Fannon M.Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky
Vitamin D binding protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors.
METHODS AND FINDINGS:In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis.CONCLUSIONS:These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of its macrophage activation.
2012 Hepatocellular Carcinoma in Mouse Model
J Surg Res. 2012 Jan;172(1):116-22.
Vitamin D binding protein-macrophage activating factor inhibits HCC in SCID mice.
Nonaka K, Onizuka S, Ishibashi H, Uto Y, Hori H, Nakayama T, Matsuura N, Kanematsu T, Fujioka H.Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan.
A high incidence of recurrence after treatment is the most serious problem in hepatocellular carcinoma (HCC). Therefore, a new strategy for the treatment of the disease is needed. The aim of the present study was to investigate whether vitamin D binding protein-macrophage activating factor (DBP-maf) is able to inhibit the growth of HCC.The effects of DBP-maf on endothelial cells and macrophage were evaluated by WST-1 assay and phagocytosis assay, respectively. Human HCC cells (HepG2) were implanted into the dorsum of severe combined immunodeficiency (SCID) mice. These mice were divided into control and DBP-maf treatment groups (n = 10/group). The mice in the treatment group received 40 ng/kg/d of DBP-maf for 21 d.
RESULTS:DBP-maf showed anti-proliferative activity against endothelial cells and also activated phagocytosis by macrophages. DBP-maf inhibited the growth of HCC cells (treatment group: 126 ± 18mm(3), untreated group: 1691.5 ± 546.9mm(3), P = 0.0077).
Histologic examinations of the tumors revealed the microvessel density was reduced and more macrophage infiltration was demonstrated in the tumor of mice in the treatment group.
CONCLUSION:DBP-maf has at least two novel functions, namely, an anti-angiogenic activity and tumor killing activity through the activation of macrophages. DBP-maf may therefore represent a new strategy for the treatment of HCC.
Bill Sardi Article
Real Help for Cancer? by Bill Sardi and Timothy HubbellThe weekly injection of just 100 billionths of a gram of a harmless glyco-protein (a naturally-produced molecule with a sugar component and a protein component) activates the human immune system and cures cancer for good, according to human studies among breast cancer and colon cancer patients, producing complete remissions lasting 4 and 7 years respectively. This glyco-protein cure is totally without side effect but currently goes unused by cancer doctors..
Normal Gc protein (also called vitamin D binding protein), an abundant glyco-protein found in human blood serum, becomes the molecular switch to activate macrophages when it is converted to its active form, called Gc macrophage activating factor (Gc-MAF). Gc protein is normally activated by conversion to Gc-MAF with the help of the B and T cells (bone marrow-made and thymus gland-made white blood cells).
But, as researchers explain it themselves, cancer cells secrete an enzyme known as alpha-N-acetylgalactosaminidase (also called Nagalase) that completely blocks conversion of Gc protein to Gc-MAF, preventing tumor-cell killing by the macrophages.
This is the way cancer cells escape detection and destruction, by disengaging the human immune system. This also leaves cancer patients prone to infections and many then succumb to pneumonia or other infections.The once-weekly injection of minute amounts of Gc-MAF, just 100 nanograms (billionths of a gram), activates macrophages and allows the immune system to pursue cancer cells with vigor, sufficient to produce total long-term cures in humans.Nobuto Yamamoto, director of the Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, Philadelphia, Pennsylvania, says this is “probably the most potent macrophage activating factor ever discovered.”–
2008 – Yamamoto Prostate Cancer Human Trial Free Full Text
free full text
Transl Oncol. 2008 Jul;1(2):65-72.
Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF.by Yamamoto N, Suyama H, Yamamoto N. Source Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA
Abstract Serum Gc protein (known as vitamin D(3)-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent MAF (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages activated by GcMAF develop a considerable variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal. Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF. As the MAF precursor activity increased, their serum Nagalase activity decreased. Because serum Nagalase activity is proportional to tumor burden, the entire time course analysis for GcMAF therapy was monitored by measuring the serum Nagalase activity. After 14 to 25 weekly administrations of GcMAF (100 ng/week), all 16 patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor-free. No recurrence occurred for 7 years.Prostatic cancer diagnosis and prognosis have been aided by the availability of PSA measurement . When patients received radical prostatectomy, a sudden drop of high PSA levels to very low values was observed (Table 1). Thus, PSA is predominantly produced from primary tumor lesions in prostate compared with the metastasized lesions. Although serum Nagalase decreased during GcMAF therapy of patients with tumor-bearing prostate, PSA remained unchanged (Table 3). Therefore, PSA values cannot be used for prognostic assays during GcMAF therapy.2008 Yamamoto Human Trial GCMAF in Metastatic Colorectal Cancer
Cancer Immunol Immunother. 2008 Jul;57(7):1007-16.
Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF. by Yamamoto N, Suyama H, Nakazato H, Yamamoto N, Koga Y. Division of Cancer Immunology and Molecular Immunology, Socrates Institute for Therapeutic Immunology, 1040, 66th Ave, Philadelphia,
Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 microg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/ human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells.
As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32-50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients.
Jeffrey Dach MD
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