Removed from Pubmed because of suspiion of scientific fraud: Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF.

Average: 7.5 (4 votes)

Transl Oncol. 2008 Jul;1(2):65-72.

Removed from because of suspected sientific fraud: Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF.

Yamamoto N, Suyama H, Yamamoto N.

Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA 19126-3305, USA.

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.


Mikael Nordfors's picture

Gc-MAF in treatment of prostate cancer: Part II

We have been kindly advised of the fact that the full text of the Yamamoto et al. paper on treatment of men with prostate cancer with Gc-MAF is available on line on the Translational Oncology web site.

In our prior commentary, based exclusively on the abstract of this paper, we had asked the following questions:

  • What was the clinical stage, grade, etc., for the 16 patients at the time of their treatment with Gc-MAF?
  • What other treatments (if any) did they have before or after treatment with Gc-MAF?
  • When were they actually treated and have other patients been treated subsequently?
  • How were they followed up?
  • What is meant by the phrase “no recurrence” in the abstract?
  • Is a Nagalase level comparable to that of a healthy control in a patient previously diagnosed with prostate cancer actually sufficient evidence that that patient is “tumor-free”?

The full text allows us to answer many (but not all) of these questions.

  • The 16 patients were all Japanese men, aged between 46 and 76 years at the time of their initial diagnosis, treated in Japan. However, the dates of treatment are not available.
  • At the time of diagnosis, the men’s PSA levels ranged from 2.5 to 68.4 ng/ml.
  • Of the 16 men, 9 had received a radical prostatectomy at some time in the past and 12 had received some (unspecified) form of hormone therapy; no patient appears to have received radiation therapy at any time.
  • Of the 9 men who received a radical prostatectomy, all 9 achieved a PSA level ? 0.3 ng/ml immediately post-surgery and 5/9 achieved a PSA level ? 0.1 ng/ml.
  • Immediately preceding treatment with Gc-MAF the patients’ PSA levels ranged from 0.09 to 21.7 ng/ml.
  • No patient had evident metastatic disease, based on the results of a CT scan immediately prior to Gc-MAF treatment.
  • There is no information given regarding the time from initiation of prior therapies to initiation of Gc-MAF treatment.
  • Immediately prior to treatment, all 12 patients had serum Gc activity levels ranging from 16.9 to 77.8 percent of the average serum Gc level of a group of seven healthy controls.
  • Furthermore, the lower a patient’s pre-treatment serum Gc level, the higher his Nagalase level.

As previously discussed, all patients were treated once weekly with 100 ng/ml of Gc-MAF for a period ranging from 14 to 25 weeks. Results following that treatment can now be fully summarized as follows:

  • There was a clear, linear correlation between serum Gc activity and Nagalase activity over time; the Nagalase activity fell as MAF precursor activity rose.
  • All 16 men had their Nagalase activities reduced to that of a normal healthy control by the time that Gc-MAF therapy was stopped.
  • In 7 years of follow-up, no patient showed a recurrence of elevated Nagalase activity.
  • In 7 years of follow-up, no patient showed any sign of metastatic disease on a CT scan
  • No information is provided about the PSA levels of the patients over the 7 years of follow up (which is perhaps unfortunate).
  • In men who had received a prior radical prostatectomy, there was a clear correlation between declining Nagalase activity and declining PSA levels over the course of treatment. However, in the men who had not received a radical prostatectomy, while Nagalase activity fell, the PSA level remained stable.
  • No information is provided about the overall survival of these 16 men since the initiation of treatment.

What is one to make of this paper?

Well in the first place it would be naive to not to take it seriously. Something is clearly happening! And if at least one drug company doesn’t pick up on this research, I would be disappointed (but then that wouldn’t be the first time!) Secondly, it seems likely to me that some of the data not provided in this paper is available somewhere. We still don’t know, for example:

  • The clinical stages of the patients at diagnosis
  • The form(s) of hormone therapy given
  • Whether the men who had had or were receiving hormone therapy continued on hormone therapy after Gc-MAF treatment
  • The patients’ post-treatment PSA levels over time
  • The patients’ long-term outcomes over time

We are then faced with the question “What is a cure?” If these 16 men all really had stable disease for a minimum of 7 years, with no progression, and no other therapy following 14-25 weeks of Gc-MAF treatment, that certainly sounds like a remarkable outcome to me!

One last thing, just so that it is absolutely clear. Gc-MAF is not patient specific. In other words (unlike biologics like sipuleucel-T), it does not have to be extracted from the serum or tissues of the individual patient. In this trial, the serum required to make the Gc-MAF used to treat the patients was simply donated by members of the staff of the Socrates Institute.

Mikael Nordfors's picture

Cancer Immunology, Immunotherapy
© The Author(s) 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

Ana Ugarte , Gauthier Bouche1 and Lydie Meheus1
The Anticancer Fund, Boechoutlaan 221, 1853 Strombeek-Bever, Belgium
Ana Ugarte
Received: 25 June 2014Accepted: 9 July 2014Published online: 24 July 2014
Without Abstract
Computerized tomography
Gc protein-derived macrophage-activating factor
Institutional Review Board
Macrophage-activating factor
This comment refers to the article available at: http://​dx.​doi.​org/​10.​1007/​s00262-007-0431-z.


Dear Editors,


After several patients asked our organization, the Anticancer Fund, www.​anticancerfund.​org, about GcMAF as a cancer treatment, we looked for the evidence supporting its use in cancer. The literature showed us striking issues and inconsistencies. We would like to comment on the article from Yamamoto et al. published in your journal in 2008 [1].


It is claimed that eight colorectal cancer patients were successfully treated with GcMAF, a protein claimed to be discovered by the authors. “Treatment success” was determined by Nagalase in serum. Nagalase is supposed to deglycosilate naturally occurring GcMAF in cancer patients so that it is incapable of activating macrophages to fight cancer. GcMAF manufactured by Yamamoto might be unaffected by Nagalase.


This article was published in parallel to two other articles by the same group in other journals, claiming that their product (GcMAF) successfully treated prostate [2] and breast cancer [3]. In 2009, they published another article reporting that GcMAF successfully treated HIV, again determining success with Nagalase [4]. In the cancer-related articles, the authors claim Nagalase is exclusively produced by cancer cells as opposed to the HIV-related article where they claim Nagalase is a viral component.
The authors do not give the most basic information on the disease of these patients: No TNM, no stage, no histology. They determined that these patients had metastatic disease, based exclusively on an elevated level of serum Nagalase. Nagalase is not a criterion to define metastatic disease in the TNM classification of cancer [5]. No key opinion leader has validated its use in oncology.


The claim “Although their serum Nagalase activities indicated that they have significant amounts of metastasized tumor cells, CT did not detect metastasized tumor lesions in other organs” means these patients did not have residual disease before starting GcMAF. All evidence cited to justify Nagalase use in this trial is publications by the same group (33 references that are cited 155 times against the 18 times the remaining 15 references are).


We have found the following about Yamamoto’s work:
The Nagasaki and the Hyogo Immunotherapy Research Groups, that gave IRB approval for these trials, do not exist except in Yamamoto’s clinical papers. Three purported members of these groups, including one chairman, informed us they are not part of these groups and that they have never been involved in Yamamoto’s activities. Other members of these IRBs could not be found.
Yamamoto’s co-authors in these papers could not be found.
We contacted the sponsors of these trials (US Public Health Service and the Elsa U. Pardee Foundation), and we found that they did not support them. They only supported Yamamoto’s early preclinical work while he was affiliated to other institutions rather than his Socrates Institute for Therapeutic Immunology.


This article also contains many mistakes and uses invalid endpoints:
Many references are used inappropriately and most do not support the authors’ claims. For example: The assertion “Administration of 100 nanogram (ng) GcMAF to humans results in the maximal activation of macrophages with 30-fold increased ingestion index and 15-fold increased superoxide-generating capacity” has no basis. This statement is supported by reference 33, which is an animal experiment in which these numbers are not mentioned. Furthermore, it has been demonstrated that naturally occurring GcMAF in cancer patients has a concentration of approximately 4 mg/L, making the 100 ng proposed by Yamamoto meaningless, plus it is not deglycosilated [6].
Without adequate randomized controlled clinical trials, the assertion “Since the molecular structure of GcMAF is identical to that of the native human MAF, GcMAF (even 5-fold higher therapeutic dosage) produced no side effects” is wrong and dangerous. It is well established that injection of some human products (i.e., insulin and epinephrine) into patients can be lethal.
The conclusions make no sense: “The curative rate measurements of tumors during GcMAF therapy and the estimation of the degree of tumor differentiation have been possible because of the availability of precision measurement of serum Nagalase”. Yamamoto proved that Nagalase failed as a disease measurement method when it was compared to CT scans at the beginning of the study. However, at the end of the study, when the CT scans matched the authors’ speculations, CT scans were again reported. The degree of tumor differentiation can only be determined by histopathology, which was not reported in this or their other articles (prostate and breast cancer articles).


These results cannot be scientifically validated as they contradict established tenets in oncology.


The Anticancer Fund is a private non-for-profit organization that provides to patients and their families evidence-based information on different cancer therapies. This organization also supports the development of cancer therapies unlikely to be profitable but that have shown promising results for cancer patients. For more information please visit our website www.​anticancerfund.​org.
Conflict of interest
The authors declare no conflicts of interest.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Yamamoto N, Suyama H, Nakazato H, Koga Y (2008) Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF. Cancer Immunol Immunother 57:1007–1016PubMedCrossRef
Yamamoto N, Suyama H, Yamamoto N (2008) Immunotherapy for prostate cancer with Gc protein-derived. Transl Oncol 1:65–72PubMedCentralPubMedCrossRef
Yamamoto N, Suyama H, Ushijima N (2008) Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Int J Cancer 122:461–467PubMedCrossRef
Yamamoto N, Ushijima N, Koga Y (2009) Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF). J Med Virol 81:16–26PubMedCrossRef
Sobin LH, Gospodarowicz MK, Wittekind C (2009) TNM classification of malignant tumors. Wiley, New Jersey

Rehder DS, Nelson RW, Borges CR (2009) Glycosylation status of vitamin D binding protein in cancer patients. Protein Sci 18:2036–2042