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GcMAF (Gc protein-derived macrophage-activating factor) is a vitamin-D binding protein that occurs naturally in the human body and plays an important role in the health of your immune system. It has various functions including activation of immune defense cells and anticancer activities [1].

Overview of GcMAF Immunotherapy for Cancer

GcMAF (Gc protein-derived macrophage-activating factor) is a vitamin-D binding protein that occurs naturally in the human body and plays an important role in the health of your immune system. It has various functions including activation of immune defense cells and anticancer activities [1].

Your body produces GcMAF in order to activate macrophages, which are immune cells responsible for fighting infections, destroying cancer cells, and inhibiting tumor growth.

However, cancer cells and tumors are known to secrete an enzyme called nagalase, which blocks the production of GcMAF in the body and prevents the immune system from attacking cancer cells [2]. As cancer develops, nagalase levels have been shown to build up in the blood of cancer patients, which results in the deactivation of macrophages, suppression of the immune system, and disease progression [3] [4].

Immunotherapy is a new strategy in the treatment of cancer and an emerging area of cancer research [1]. GcMAF was discovered in the 1980s by Nobuto Yamamoto, while the first research papers showing its immune stimulating and antitumor effects were published in the 1990s. It is a promising yet unapproved immunotherapy with the reported ability to act as a macrophage activating agent in the treatment of cancer [5].

There is scientific evidence to support its potential efficacy and safety as an immunotherapy in small-scale human studies, but there has been controversy surrounding the treatment and some researchers are skeptical [5]. Large-scale clinical research is still needed and the long-term effects are currently unknown.

Historical Perspective of GcMAF Immunotherapy for Cancer

The idea of stimulating the immune system to treat cancer dates back to the early 1900s, but it was not until the 1950s with the discovery of tumor-specific antigens (substances that activate an immune response against tumors) that there was a resurgence of medical interest into immune therapies [6].

To understand the origins of GcMAF as an immune therapy for cancer we have to go back to the late 1980s in Philadelphia, USA. At this time, Dr. Nobuto Yamamoto, PhD, a well respected US-based Japanese researcher, wrote a paper on blood components involved in the activation of macrophages [7].

This study would form the basis of later research papers, which proposed that GcMAF was the natural activator of macrophages in mammals and that injection of GcMAF may enhance the immune response to cancer in humans [8] [9]. Yamamoto carried out studies on GcMAF in mice with Ehrlich ascites tumor (aggressive type of cancer) and demonstrated significantly increased survival rates [10].

In 2008/2009 Yamamoto published four papers claiming successful treatment of cancer and HIV patients with GcMAF [11] [12] [13] [14]. The results appeared too good to be true. Later, in 2014, the Anticancer Fund non-profit educational and research support organization wrote a letter highlighting inconsistencies and major issues with Yamamoto’s research [15]. Three out of the four studies were retracted due to the use of unestablished metrics (such as serum nagalase levels) to define successful treatment, which could not be accepted by the scientific community.

Despite controversy and reported problems with Yamamoto’s later work, there has been ongoing research into the use of GcMAF as an immunotherapy for many different cancer types in small-scale case studies in patients [5]. Some researchers remain optimistic about the potential of medications like GcMAF, which can inhibit immunosuppressive factors such as the enzyme nagalase [5].

A 2022 review of Yamamoto’s research on GcMAF claims that his work deserves widespread renewed attention both for cancer and HIV treatment [6]. According to the reviewer, Yamamoto’s data demonstrates that GcMAF is a highly specific activator of macrophages with the therapeutic potential to reduce nagalase levels in cancer patients [6].

Research about GcMAF Immunotherapy for Cancer

GcMAF has shown some promise of efficacy and safety in humans, but only in studies of questionable quality due to the use of unconventional metrics to evaluate results and with small sample sizes. There has been controversy and issues flagged with some of the scientific research on GcMAF [16]. Double-blind randomized clinical trials with larger sample sizes (in the hundreds or thousands) are still needed to determine efficacy and long-term safety.

In 2008 Dr. Yamamoto published research on successful GcMAF treatment for patients with colon, breast and prostate cancer (stage of disease not reported) [11] [12] [13].

These studies were with small sample sizes (8 with colon cancer, 16 with breast cancer and 16 with prostate cancer). Two of the studies were later retracted. Patients had undergone conventional treatment of surgery, chemotherapy and/or radiation prior to GcMAF treatment [16]. Serum nagalase levels were used as an indicator of tumor burden. Success was claimed based on reduced nagalase levels and no tumor recurrence after many years in all patients, which was not sufficient evidence to support claims of efficacy as a primary cancer treatment [15].

A 2013 study on advanced cancer patients with diverse cancer types reported that all patients showed a significant decrease of serum nagalase activity after receiving weekly injections of GcMAF [3]. Reduced nagalase levels were associated with improved clinical conditions and no adverse effects were reported. However, the study was a non-controlled retrospective analysis and results cannot be claimed as indicative of a cause-effect relationship of GcMAF administration and improved disease outcomes [3].

A 2017 review collated results from 12 studies and case reports from 2008-2016 of GcMAF treatment for cancer patients with a range of different cancer types including colon, thyroid, lung, liver, thymus, pancreatic, bladder, ovarian and tongue [5]. The review evaluates what it deems to be credible research on the treatment. However, all studies are with very small sample sizes and many include other alternative cancer therapies, which means it is not possible to identify a single causative agent for improvement. The review states that clinical investigations have demonstrated the efficacy of GcMAF as a macrophage activating factor and calls for further research into the application of the promising new immunotherapy. The authors claim that the efficacy and safety of the drug warrants FDA approval and that there are non-scientific reasons preventing approval [5].

A 2022 critical overview of Dr. Yamamoto’s controversial studies delves deeply into his findings and calls for renewed scientific attention on research into GcMAF [6]. While Yamamoto’s claims of success and research methodology came under fire in the oncology community, his data shows direct correlation between GcMAF treatment and the activation of macrophages in cancer patients. His results also demonstrate reduction of nagalase levels after GcMAF therapy, which could indicate therapeutic potential as an immunotherapy [6].

Potential Applications of GcMAF Immunotherapy for Cancer

In the current scientific literature, the term ‘immunotherapy’ for cancer refers to a select group of treatments including immune checkpoint inhibitors, immune cell therapy, therapeutic antibodies, vaccines and immune-modulating agents - all of which have potentially serious adverse effects [6].****

Immunotherapy with GcMAF has been shown to be free from adverse effects in the research to date and shows promise in small-scale studies for diverse applications [6].** **There is some evidence to indicate that GcMAF may have therapeutic benefits for different cancer types and a wide range of other conditions including chronic obstructive pulmonary disease (COPD), endometriosis, osteoporosis, autism, and systemic lupus erythematosus (SLE) [2]. However, there is low certainty surrounding efficacy and safety due to a lack of definitive clinical evidence.

Patient selection is important when it comes to GcMAF therapy as the antitumor effects of the treatment vary depending on the type of cancer and stage [5]. Preliminary research shows potential benefits for patients with prostate, breast, colon, liver, stomach, lung (including mesothelioma), kidney, bladder, uterus, ovarian, head/neck and brain cancers, fibrosarcomas and melanomas [5].

GcMAF has been reported to have better results in the treatment of undifferentiated tumor cells (such as adenocarcinoma) than with differentiated cells (such as squamous carcinoma cells) in test tube studies and also in patients [3] [5]. Anemia and other blood disorders can confound the efficacy of GcMAF. Therefore, the treatment has been indicated for non-anemic patients only [5].

In the last decade, the existence of cancer stem cells (tumor cells that can drive new tumor growth and cause relapses) has been demonstrated and may explain why recurrence is frequently observed after conventional cancer treatments. Research into GcMAF shows that it could help in the elimination of the last residual cancer stem cells and serve to prevent disease recurrence [6].

GcMAF may also be of benefit for patients with advanced or resistant cancer where conventional treatment has not been successful. However, for the therapy to be effective it is important that the patient's immune system is still intact [6]. Furthermore, given that the immune system has a limited ability to break down and eliminate large tumors, surgery or radiation to remove the bulk tumor mass is generally required prior to GcMAF immunotherapy [6].

In summary, there is early evidence to suggest that GcMAF could be used in the treatment of cancer to modulate the immune system and prime it to eliminate cancer cells. However, any claims of a wonder molecule that is a safe and effective cancer treatment in its own right are unfounded. Preliminary research supports its potential application as an immunotherapy to help prevent recurrence after standard of care treatments. However, further clinical research is still needed.

Risks and Side Effects of GcMAF Immunotherapy for Cancer

To date there have been no adverse effects reported in the scientific literature from the use of GcMAF in small studies in humans [5] [6]. Early research indicates that it may be safe, but the treatment is considered experimental at this stage. Given that GcMAF is not FDA approved there could be risks of contamination and other confounding factors. Long-term clinical studies have not been carried out to prove safety. Therefore, safety and risks of side-effects are currently unknown.

Frequently asked questions about GcMAF

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The Best 9 Integrative Cancer Treatment Centers that offer GcMAF

References of GcMAF

[1] Inui, T., Makita, K., Miura, H., Matsuda, A., Kuchiike, D., Kubo, K., ... & Sakamoto, N. (2014). Case report: a breast cancer patient treated with GcMAF, sonodynamic therapy and hormone therapy. Anticancer research, 34(8), 4589-4593.

[2] Saburi, E., Tavakol-Afshari, J., Biglari, S., & Mortazavi, Y. (2017). Is α-N-acetylgalactosaminidase the key to curing cancer? A mini-review and hypothesis. J BUON, 22(6), 1372-1377.

[3] Thyer, L., Ward, E., Smith, R., Branca, J. J., Morucci, G., Gulisano, M., ... & Pacini, S. (2013). GC protein-derived macrophage-activating factor decreases α-N-acetylgalactosaminidase levels in advanced cancer patients. Oncoimmunology, 2(8), e25769.

[4] Eric Matamoros, M. (2017). GcMAF: a polemic or a highly promising molecule?. World Scientific News, 65, 20-36.

[5] Saburi, E., Saburi, A., & Ghanei, M. (2017). Promising role for Gc-MAF in cancer immunotherapy: from bench to bedside. Caspian Journal of Internal Medicine, 8(4), 228.

[6] Albracht, S. P. (2022). Immunotherapy with GcMAF revisited-A critical overview of the research of Nobuto Yamamoto. Cancer Treatment and Research Communications, 100537. ]([

[7] Yamamoto, N., Ngwenya, B. Z., Sery, T. W., & Pieringer, R. A. (1987). Activation of macrophages by ether analogues of lysophospholipids. Cancer Immunology, Immunotherapy, 25(3), 185-192. ]([

[8] Yamamoto, N. (1996). Structural definition of a potent macrophage activating factor derived from vitamin D3-binding protein with adjuvant activity for antibody production. Molecular immunology, 33(15), 1157-1164. ]([

[9] Yamamoto, N., & Naraparaju, V. R. (1998). Structurally well defined macrophage activating factor derived from vitamin D3 binding protein has a potent adjuvant activity for immunization. Immunology and cell biology, 76(3), 237-244.

[10] Yamamoto, N., & Naraparaju, V. R. (1997). Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer research, 57(11), 2187-2192.

[11] Yamamoto, N., Suyama, H., & Yamamoto, N. (2008). Immunotherapy for prostate cancer with Gc protein-derived macrophage-activating factor, GcMAF. Translational oncology, 1(2), 65-72. ]([

[12] Yamamoto, N., Suyama, H., Nakazato, H., Yamamoto, N., & Koga, Y. (2008). RETRACTED ARTICLE: Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF. Cancer Immunology, Immunotherapy, 57(7), 1007-1016. ]([

[13] Yamamoto, N., Suyama, H., Yamamoto, N., & Ushijima, N. (2008). Retracted: Immunotherapy of metastatic breast cancer patients with vitamin D binding protein derived macrophage activating factor (GcMAF). International journal of cancer, 122(2), 461-467.

[14] Yamamoto, N., Ushijima, N., & Koga, Y. (2009). Retracted: Immunotherapy of HIV infected patients with Gc protein derived macrophage activating factor (GcMAF). Journal of medical virology, 81(1), 16-26.

[15] Ugarte, A., Bouche, G., & Meheus, L. (2014). Inconsistencies and questionable reliability of the publication “Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophages-activating, GcMAF” by Yamamoto et al. Cancer Immunology, Immunotherapy, 63(12), 1347-1348. ]([

[16] Arney, K., (2008). “Cancer cured for good?” – Gc-MAF and the miracle cure. Cancer Research UK, [Updated 10/05/15].

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