Note: This post has been updated as several research papers about Gc-MAF have been retracted. We will continue to update this post as more information becomes available. Last update 05/10/15.
As an organisation dedicated to beating cancer, we have a deep-rooted interest in any new research developments that could lead to new, more effective treatments for the disease.
So when we received an enquiry from a supporter about an article entitled “Cancer cured for good” by Bill Sardi and Timothy Hubbell* we were intrigued. The article talks about research by Nobuto Yamamoto in the US, looking at a protein called Gc-MAF (aka GcMAF). His published studies appear to show that injections of very small amounts of Gc-MAF can “cure” people with breast, bowel and prostate cancer.
According to the article, “It works 100% of the time to eradicate cancer completely, and cancer does not recur even years later.” Could this be the so-called ‘cure for cancer’ that we’ve been searching for all these years?
Sadly – as with so many things in life – if it sounds too good to be true it probably is. Major questions are now being raised about Gc-MAF (for example, this investigation by the BBC) and the companies that sell it, and it is not licensed in the UK to treat any disease. [Updated KA 01/10/15]
Let’s explore a bit further.
What’s the idea behind it?
Dr Yamamoto studies the immune system – the highly complex network of cells that helps to keep us healthy. The cells of the immune system – white blood cells – fight bacterial and viral infections because they can recognise and attack these ‘foreign’ invaders . But they’re not so good at tackling cancer, since tumours grow from our own cells and have clever mechanisms to ’cloak’ them from immune attack.
Macrophages (meaning “big eaters” in Greek) are an important type of white blood cell. They patrol the body, eating up foreign invaders and dead cells. They also help to alert other immune cells to the presence of infections.
Macrophages can be stirred into action by a small sugar-coated protein (glycoprotein) called Gc-MAF, short for Gc Macrophage Activating Factor, which is produced by the body. But it’s thought that the production of Gc-MAF is blocked by an enzyme called Nagalase (alpha-N-acetylgalactosaminidase), produced by many cancers. This is one of the mechanisms that helps tumours evade the immune system.
Yamamoto’s theory is that injecting cancer patients with Gc-MAF should activate their macrophages to fight the cancer. He tested it back in 1997 in a paper published in the journal Cancer Research, showing that injecting Gc-MAF into mice transplanted with cancer cells could improve their survival from around 16 days to around 35.
But the treatment did not ‘cure’ the cancer, as the cancer cells continued to multiply, eventually killing the animals.
However, there are questions about the science underpinning the idea that Gc-MAF can treat cancer. For example, other researchers have found no differences in the levels of Gc-MAF between cancer patients and healthy people – and the levels they do find are far higher than the very small doses proposed to work by Yamamoto. It’s hard to see exactly how this finding fits with the idea of how the treatment is supposed to work, and it doesn’t support the use of Gc-MAF as a treatment for cancer. [Updated KA 05/10/2015]
Fast-forward a few years, to the publication of three papers detailing the results of clinical trials of Gc-MAF carried out by Yamamoto, testing the treatment on patients with breast, bowel and prostate cancer.
Note: The breast cancer paper (Yamamoto et al Int J Cancer 2008) has now been retracted, due to various concerns with the work. Read more on the RetractionWatch blog. [Updated KA 25/07/14] The bowel cancer paper (Yamamoto et al Cancer Immunology Immunotherapy 2008) has also now been retracted. This letter details some of the concerns about the work. [Updated KA 09/10/14]
The results appear to be startling – all the patients on the trials are ‘cured’ of cancer. Surely this is an amazing breakthrough?
Put bluntly, no it isn’t. There are significant scientific problems with the trials. For a start, all the studies are very small, involving fewer than twenty patients in each – rather than the thousands needed to make the sort of claims mentioned above.
Next, all the patients involved had received standard treatment for their cancer, including surgery, chemotherapy and/or radiotherapy. This is a somewhat unorthodox design for a trial of this kind, because it makes it very difficult to tell if any successes are due to the new drug, or the more conventional treatments.
On top of this, the researchers didn’t actually monitor the progress of tumours in the patients, and provide no clinical information about them. Instead they opt to measure levels of Nagalase in the blood, rather than looking at any standard established markers for cancer.
For example, in the case of the breast cancer patients, there is no detail about their “TNM” (tumour, node, metastasis) status. This is a standard measure of how far a patient’s cancer has spread, and is used to calculate the likelihood that it will return.
Furthermore, the researchers didn’t do any tests to show that injected Gc-MAF was actually activating macrophages in the patients’ blood, or even working in the way that they expect. There is no information about levels of cytokines – the proteins produced by immune cells when they are activated – or analysis of the patients’ immune cells.
Perhaps most significantly, there are no controls – untreated patients for comparison – and the studies only followed the patients for a few years. We have no way of telling whether their cancers were growing again, or had been successfully treated, and whether this was due to Gc-MAF or the other treatment they had received.
Given that 80 per cent of all women with breast cancer survive for at least 5 years, an uncontrolled study showing that 16 women of unknown TNM status survive for at least 4 years is no great shakes, scientifically speaking.
Another small study of 20 patients with a range of cancers, published in 2013, has similar problems. It’s not a controlled trial, and the researchers only measure nagalase levels as an indicator of whether the treatment is ‘working’, and provide very little hard clinical data (such as scans or other recognised tests) about the patients’ actual tumours. For example, in one concerning case, although the researchers showed that an ovarian cancer patient’s nagalase levels had gone down, the levels of another marker – CA125, which is produced by ovarian cancer cells – had gone up. Yet this is classed as an “improvement” in the paper, with no other supporting information. Overall, this study is also a long way from being convincing evidence that the treatment is effective. [Updated KA 05/10/2015]
Another telling point is the type of journal in which the research was published. If this research was truly groundbreaking, and pointed the way to a cure for cancer, then the research would likely be found in top-tier ’high-impact’ medical journals journals like The Lancet, The New England Journal of Medicine or the Journal of the American Medical Association.
And finally, virtually all the references in the papers are to other papers published by Yamamoto and his team. If Gc-MAF was indeed a promising candidate for a successful cancer treatment, you’d expect plenty of other research to show the same thing. Scientists are usually quick to spot promising, emerging fields of research and jump on the bandwagon.
The poor quality of scientific papers supporting GcMAF is discussed here on the Scholarly Open Access blog. [Updated KA 25/07/14]
Is there hope?
Although this particular approach isn’t all it’s hyped up to be, harnessing the power of immune system could be a very potent way to treat cancer. We’ve blogged many times already on high-quality research into immunotherapy (for example here, here, here and here)
And many Cancer Research UK-funded scientists are also working in this field. For example, Professor Fran Balkwill and her team are working on ways to trick macrophages and other immune cells into attacking cancer cells.
In 2014, researchers in Israel started a small-scale early-stage clinical trial looking at the dosage and safety of GcMAF in cancer patients. The full protocol and further information are available on the Clinicaltrials.gov register. [Updated KA 25/07/14]
To sum up
The advent of the internet has led to a wild proliferation of stories of ‘miracle cures’ for cancer – virtually all of which are based on shaky (or zero) science.
Some companies are selling Gc-MAF for use by cancer patients. This treatment is not approved or licensed in the UK for treating cancer or any 0ther disease. Given that there is no solid scientific evidence to show that the treatment is safe or effective, we would not recommend that cancer patients use it. [Updated KA 25/07/14]
Cancer is an extremely complex disease. In fact, it is more than 200 distinct diseases, each requiring different treatment. And the success of treatment depends on many things, including the genetic make-up of the tumour, the stage of diagnosis, and how aggressive the cancer is.
To suggest that there is a ‘magic bullet’ that cures all cancers is simplistic in the extreme.
More information and updates:
- Anticancer Fund: GcMAF information
- Yamamoto’s 2008 paper on Gc-MAF and HIV has also now been retracted by the journal.
- The Medicines and Healthcare Regulatory Authority (MHRA) has closed down a factory in Cambridge making Gc-MAF, following concerns about the quality and safety of the products – principally that they were unfit for use in humans. [Updated KA 31/07/15]
- The First Immune clinic in Bussigny, France, offering Gc-MAF treatment has been closed down after several cancer patients died (story is in French). [Updated KA 31/07/15]
- BBC 5Live Investigates: Unlicensed blood drug GcMAF still for sale. [Updated KA 01/10/15 ]
*Cancer Research UK is not responsible for the content of external websites. This is not an endorsement of the website by Cancer Research UK. The original page has been taken down – the link in this post is from the Internet Archive (captured February 2009) [Updated KA 01/10/15]
Henry Scowcroft June 30, 2009
Regretfully, we have closed comments on this thread.
This is not to intentionally to stifle debate around this issue, which is obviously something many feel passionately about (including ourselves). As a charity dedicated to evidence-based science, we absolutely feel that debate and discussion of scientific issues is key to improving cancer treatment and awareness of issues surrounding the disease. That is why we started writing this blog.
Recently, however, we have had to increasingly delete and moderate attempts to post links to websites selling Gc-MAF, and to promote its use to treat cancer. Neither of these is something we’re comfortable with, given the current state of evidence surrounding Gc-MAF. As we’ve repeatedly said above, we believe there are substantial shortcomings with the evidence base around this substance, and until these are clarified, we cannot recommend anyone, anywhere, considers it as a serious treatment option.
We hope you understand, and apologies once again.
Henry, Kat and Ed
visonetto May 29, 2009
The Hiv Eradication article pubblished by prof. Yamamoto on January 2009 on the scientific Journal Medical Virology, has had little feedback…better say, no feedback at all even by the national and international press too.
This fact is very strange!
Only some associations have posted the news on their home-pages but the news has dropped away without any feedback.
Some Hiv+ people have activated a series of initiatives to contact the directors of the JMV, responsable of the publication.
The publication of Prof. Yamamoto is rich of significant data and descriptive tables about the research and are of a big impact.
The directors of the magazine, Prof. Zuckerman and Prof. Mahny have answered to the questions, guaranteeing the validaty of the data, eventhough in an elusory way, but at the same time threatening to sue us without any reason. The questions were legitimate and politely done!
Is it possible that nobody wants to comment this article of such a big impact!?
Anyway it has been prepared the following e-mail and sent to the most prestigious agencies.
Dear director of Aids Operative Centre.
more than 4 months ago has been possible to notice the publishing, on the scientific Jornal Medical Virology, an article on HIV eradication by Prof. Yamamoto, explaining the way he obtained the Hiv eradication in only 18 weeks by injecting, weekly, 100ng GcMAF, an activating factor of macrophages obtained by the Gc Protein. This is shown by a fully successfull experiment, done in 2002 on 15 assintomatic Hiv+ patients and non anemic one; these patients have been healthy without having a viral feedback (HIV-RNA, HIV-DNA) and immune alterations such as CD4, CD8 and their percentage absolutely normal) in more than seven years (J. Med. Virol. 81:16-26, 2009).
We have been trying to inquire with the help of the associations, specialists and even embassys without having a feedback, particularly:
1 – [authorised ethic committees]
2 – [centres and patients]
3 – [contacts with the authors]
4 – [contacts with the directors of JMV]
Now, since the issue continues to cause serious disturbance among all the Hiv+, and we are not in the best possible conditions, we ask to You and to Your Institution, authority of national importance, to clear up the points above, in order to ascertain whether we are faced with a falsely clamorous scientific discovery or a true one.
Certainly we would like to see confirmed the latter one. We are convinced that you would put under exam the GcMAF, a low-cost molecule and of an easy preparation, for further clinical trial in case of the results of Prof Yamamoto would be authentic. This would represent the salvation of millions of Hiv+ people all over the world.
Dispite the disappointment in case the trial is not true, we are greatful to You for having provided to us an answer.
Hopefully in an acceptance of our request, we thank and cordially greet.
An Hiv+ patient.
Kat Arney May 29, 2009
Thanks for your comment. We appreciate the interest in Yamamoto’s claims about HIV, but as publicly-funded charity dedicated to cancer research, our work must necessarily focus on cancer.
We do not directly commission research projects – our funds are awarded through a competitive grant process http://science.cancerresearchuk.org/gapp/ If a researcher wished to carry out work in the UK on Gc-MAF’s potential for treating cancer, they would need to apply to the appropriate Cancer Research UK committee. Their application would then be judged by a panel of national and international experts – as all grant applications are. We will only fund work that is highly competitive, and at the forefront of research into cancer.
John Page April 15, 2009
Alot of smart people say cancer is 100 different deseases………I don’t think so. In my heart its one desease that may attack 100 different places.The idea that the immune system in some people isn’t doing its job, makes sence to me.
By the way my daughters chemo was changed and her second round was not as bad. None the less we are also taking extra measures ie. diet no sugars , ozone treatments….ground up flax seed, better water. Maybe zeolite coming next.
Sure hope this Gc-MAF gets off the ground and get rid of chemo……like DDT it should be banned!
northsouth March 30, 2009
Are macrophages the strongest human’s weapon to beat the cancer ? ..probably yes.
Dr Zengh Cui and Mark Willingham
Dr Zengh Cui research makes Yamamoto’s MAF declaration stronger and stronger.
More recent studies, described in the May 8, 2006, Proceedings of the National Academy of Science USA, demonstrated the ability to cure cancer in normal mice by transferring purified immune cells from the cancer-resistant mice. These newer studies show that specific types of innate immune cells, such as macrophages, can migrate to the site of cancer in a normal mice and selectively kill all of the cancer cells without harming normal cells. Such studies suggest that this type of mechanism might one day be able to help design a new strategy for cancer therapy.
Transferable anticancer innate immunity in spontaneous regression/complete resistance mice
Amy M. Hicks*, Gregory Riedlinger†, Mark C. Willingham*, Martha A. Alexander-Miller‡, C. Von Kap-Herr§, Mark J. Pettenati§, Anne M. Sanders*, Holly M. Weir*, Wei Du*, Joseph Kim*, Andrew J. G. Simpson¶, Lloyd J. Old¶,‖, and Zheng Cui*,‖
Departments of *Pathology,
†Cancer Biology, and
‡Microbiology and Immunology, and
§Department of Pediatrics, Section on Medical Genetics, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and
¶Ludwig Institute for Cancer Research, New York, NY 10158
Contributed by Lloyd J. Old, March 28, 2006
Spontaneous regression/complete resistance (SR/CR) mice resist very high doses of cancer cells that are lethal to WT mice even at low doses. In this study, we show that this resistance is mediated by rapid infiltration of leukocytes, mostly of innate immunity, in both primary and repeated challenges. Formation of rosettes with infiltrating natural killer cells, neutrophils, and macrophages was required for the subsequent destruction of cancer cells through rapid cytolysis. Highly purified natural killer cells, macrophages, and neutrophils from the SR/CR mice independently killed cancer cells in vitro. The independent killing activity by each subset of effector cells is consistent with the observation that the resistance was abolished by depleting total infiltrating leukocytes but not by depleting only one or two subsets of leukocytes. The resistance was completely transferable to WT recipient mice through SR/CR splenocytes, bone marrow cells, or enriched peritoneal macrophages, either for prevention against subsequent cancer challenges or eradication of established malignancy at distant sites.
alcohol detox March 26, 2009
Many people are being cured of cancer by other means.
Yamamoto’s theory is that injecting cancer patients with Gc-MAF should activate their macrophages to fight the cancer. He tested it back in 1997 in a paper published in the journal Cancer Research, showing that injecting Gc-MAF into mice transplanted with cancer cells could improve their survival from around 16 days to around 35.
John Page March 17, 2009
But now Im back to square one….I don’t suppose I can get this Gc-MAF.
My daughter’s blood count went down to .3 after her first chemo. Im looking outside the box for sure….she doesn’t want chemo again.
What now….some say go to Mexico others Mushroom extract….some Keelation using Zeolite to purge the body of metals.
Gc-MAF looked like my best bet!
Kat Arney March 18, 2009
I’m very sorry to hear about your daughter. There is an awful lot of information out there on the internet about cancer treatments and cures, and not all of it is reliable. Many so-called “cures” are not based on sound science and have not been tested in clinical trials – there is no guarantee they will do any good, and at worst they could be harmful.
There’s lots more information about alternative and complementary treatments on our CancerHelp UK website: http://cancerhelp.cancerresearchuk.org/about-cancer/treatment/complementary-alternative/
I would also strongly recommend that you look at Quackwatch to see if they have anything to say about potential avenues you may be looking at, to see if they could be dangerous, fraudulent or simply ineffective:
Best wishes to you and your family,
John Page March 16, 2009
Im trying to understand all this…let me know if im right.
Gc-MAF is actually vitamin D3….is that correct
It may boost your immune system by blocking an ensyme called nagalese and let your natural defences ie. white blood cell (macrophages) do the cancer killing?
Kat Arney March 17, 2009
John – close but not quite!
Gc-MAF is not vitamin D. Gc-MAF is a protein made by natural chemical changes to another protein in our bodies called “vitamin D binding protein” . One of vitamin D binding protein’s jobs in the body is to help us absorb vitamin D – but that’s not really important in this story.
As we explained in the post, scientists think that Gc-MAF (naturally produced by the body) activates special white blood cells, macrophages, that then can eat up cancer cells. But these cancer cells can produce another protein called nagalase, which seems to stop the body turning vitamin D binding protein into Gc-MAF. If this is true, this is bad news, as then Gc-MAF can’t activate macrophages, and the cancer can grow.
Dr Yamamoto’s idea is that injecting cancer patients with extra Gc-MAF will compensate for this, causing macrophages to be activated and killing the patient’s cancer cells.
As we’ve explained in the post, this is an intriguing idea, although there are flaws in the research done so far. It’s an interesting avenue of research, but it’s certainly not the 100 per cent cancer cure that is being claimed by some reports.
John Page March 12, 2009
You all seem quite intelligent… maybe a little to smart (I’ll explain).My daughter has breast cancer and is now in ICU after her first chemo….not good.
I think the idea of killing the cancer hopefully before killing the patient is retarded. After all the time and money spent on this ….is that the best we can do. Is it all about drug companys making billions…Im starting to wonder. Everyone seems well intentioned…..but big deal. Doctors know what they are taught…so I figure some neanderthal must have started all this.
Oh ya ….why I say maybe to smart.A while back their was a tadio talk show with a foot specialist as the guest . The subject turned to athelets foot which interested me cause I had it and couldn’t get rid of it with all the pharmacy crap. An old guy phoned in and said “pee in a bucket…put your foot in and wiggle your toes”. The specialist had never heard such a thing…guess what I did it and IT WORKS!
Excuse the sheppling….I ain’t to smart
northsouth February 9, 2009
I have read some opinions about Yamamoto’s research that was pubblished in The Journal of medical virology january 2009.
Yamomoto’s study deserves far more than the weak brief once-over given to it by CATIE.
Yamamoto’s scientific background is impressive.
Preclinical peer-review researches pubblished in Nature magazine about MAF.
Nature has extremely stringent standards for publication, and will reject papers that report good quality scientific work if editors feel the
work is not a breakthrough in the field. Such journal generally has a two-tier reviewing system. In the first stage, members of the editorial board verify
that the paper’s findings — if correct — would be ground-breaking enough to warrant publication in Nature. Most papers, more and less 95 %, are rejected at this stage. Nature publishes about 5 percent of received papere. Papers that do pass this ‘pre-reviewing’ are sent out for in-depth
review to outside referees. Even after all reviewers recommend publication and all reviewer criticisms/suggestions for changes have been met, papers may still be returned to the authors for shortening to meet the journal’s length limits.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1502120 ( the MAF
results come from other researchers in different university and hospital ).
Vitamin D Binding Protein-Macrophage Activating Factor (DBP-maf) Inhibits Angiogenesis and Tumor Growth in Mice1
Oliver Kisker,*† Shinya Onizuka,‡ Christian M Becker,*§ Michael Fannon,* Evelyn Flynn,* Robert D’Amato,*¶ Bruce Zetter,*# Judah Folkman,*# Rahul Ray,** Narasimha Swamy,†† and Steven Pirie-Shepherd‡‡
*Division of Surgical Research, Children’s Hospital, Boston, MA 02115, USA
†Department of General Surgery, University Hospital Marburg, Philipps University, Marburg, Germany
‡Department of Surgery II, Nagasaki University School of Medicine, Nagasaki, Japan
§Department of Gynecology and Obstetrics, University Hospital Benjamin Franklin, Free University Berlin, Berlin, Germany
¶Department of Ophthalmology Harvard Medical School, USA
#Department of Surgery and Cell Biology, Harvard Medical School, USA
**Bioorganic Chemistry and Structural Biology, Vitamin D Laboratory, Department of Medicine, Boston University, Boston, MA 02118, USA
††Department of Pediatrics, Brown Medical School, Providence, RI, USA
‡‡Attenuon LLC, San Diego, CA 92121, USA
Address all correspondence to: Steven Pirie-Shepherd, Attenuon, LLC, 10130 Sorrento Valley Road, Ste B, San Diego, CA 92121, USA. E-mail: [email protected]
Also corresponding author: Narasimha Swamy, Department of Pediatrics, Brown Medical School, 101 Dudley Street, Providence, RI, USA. E-mail: [email protected]
Received August 30, 2002; Accepted September 27, 2002.
Moreover the most important cancer meeting in USA.
Among the members of the Editorial Board of The Journal of Medical Virology, there is CDC of Atlanta.
It is very difficult to believe that CDC gave green light to pubblish Yamamoto’s declaration about HIV ERADICATION without scientific evidence.
I trust much more CDC than any other..
E D I T O R – I N – C H I E F
ARIE J. ZUCKERMAN
Royal Free and University College Medical School
University College London
E-Mail: [email protected]
U S E D I T O R
BRIAN W.J. MAHY
Centers for Disease Control and Prevention
E-Mail: [email protected]
Why the study and results that were pubblished in Cancer Research, Nature, The Journal of medical virology, Clinical immunology, Aids research
magazine (and many others ) has not been proved wrong yet….. ?
After 7 years the accademic questions about proviral hiv dna pcr are worthless.
Pol Fliet January 17, 2009
Can somebody tell me where i can find Gc-Maf. When it works its worth to try it.
J.A. January 8, 2009
I’m wondering if Gc-maf could theoretically cause severe inflammation in advanced cancer patients… According to scientific research, classically activated macrophages contribute to tumorigenesis.
Gonzales January 2, 2009
[Edited to add: This is a response to an enquiry cross-posted from an internet forum. Kat]
May 31, 2008
We have exhausted GcMAF stock. We hope to prepare new stock of GcMAF in a few months. We keep your information until approval for commercialization of GcMAF. However, our institute is non-profit organization and we can collaborate with your group for cancer therapy.
Incidentally GcMAF is the most powerful curative remedy for HIV disease. We are glad to help you for GcMAF therapy of tuberculosis and hepatitis.
Dr. Nobuto Yamamoto, Director
Socrates Institute for Therapeutic Immunology
Gonzales December 31, 2008
Yamamoto claims HIV eradication, aids is the late stage of hiv infection.
JA December 28, 2008
Yamamoto did not mention eradicating AIDS, but the HIV infection. I believe he was not referring to advanced full blown AIDS patients. HIV infection if diagnosed early can sometimes be managed or even eradicated. I’ve personally known a few full blown AIDS cases that were cured by various means but won’t get into that now.
The body has the ability to produce polyclonal antibodies to be able to keep up with the virus’s capacity to mutate, as long as the antigen presentation mechanism is properly functioning and T-helpers to their part. In the early stages of the infection, I do believe eradication is possible. Cancers however, in 80% of the cases, especially when diagnosed late can be much more complex to deal with.
Paul Fenwick December 24, 2008
Thanks for the link.
I have one questione. Why do they let Yamamoto pubblish that research where is written hiv can be cured ?
HIV is not a cancer and it is so easy to prove that someone has been cured …. a HIV dna/rna test is enoguh…
There are milion people in the world that have been cured from cancer…so far only a german “patient” seems to be cured from hiv.
Kat December 23, 2008
Dr Yamamoto is also investigating whether Gc-MAF can treat HIV. As this is a cancer blog, we can’t comment on that, but there is more information from the Canadian AIDS Treatment Information Exchange here.
They urge their readers to “treat these claims with a healthy degree of skepticism”.
Paul Fenwick December 23, 2008
What ….. 16 hiv infected people cured ?????
Someone can confirm that 16 hiv person have been cured ??
Yamamoto claimed HIV ERADICATION……..
Do you realize what does it mean ?
The surprising new is THE HIV ERADICATION….
Jack L. December 21, 2008
Yamamoto is a serious scientist who has only reported exactly what he has found in preclinical and clinical studies and he has never made statements such as “Cancer Cured for Good”, “miracle cure”, “miracle bullet”. It is ridiculous to quote somebody else’s statements and attribute them to Yamamoto, when he himself never made these types of statements in his publications.
1). Yamamoto’s group reported that only non-anemic patients were treated with a single remedy (GcMAF) modality. Extremely advanced cancer patients are anemic and the treatment of these patients was not included in Yamamoto’s papers. When treating cancer, any clinical (IRB-approved) results reported should demonstrate that no recurrence has occured for several years post-treatment. In Yamamoto’s studies, many patients showed no recurrence for seven to fifteen years post-treatment. Yamamoto’s group have been reporting their findings at the Annual Meetings of American Association for Cancer Research (AACR) since 1996. Yamamoto and his group monitored their patients for much longer than most published cancer therapy researchers. Proof of therapeutic efficacy of a remedy in cancer patients requires this type of long term research and follow-up before publication. If you know of any way to produce short term research that proves therapeutic efficacy in cancer patients, please post your results in this forum with the reference publication.
2). The statement that Yamamoto performed clinical studies without controls is another ridiculous statement. In the case of human cancers with a single remedy modality (such as GcMAF) therapy, the use of experimental controls without providing the study treatment is immoral (unethical). You should not perform the same experiment with cancer patients as you do in an animal studies, and any ethical scientist should know better. A control study (e. g., placebo) can only be ethically used by deleting a single new study remedy within a dual remedy modality (when a second remedy is also used in the clinical trial), so that all patients receive some form of treatment.
3). Yamamoto’s group has published a study in a murine cancer model in Cancer Res 57, 2187-2192, 1997. You should read the paper and the abstract carefully. The investigators used Ehrlich ascites tumor, the most virulent murine mammary adenocarcinoma that normally kills mice in approximately 16 days. When 100 picograms (pg) of three different MAFs (macrophage activating factors) were used in the study ( i.e., GcMAF, mouse MAF (DBPMAF), cloned domain III MAF (CdMAF)), all mice survived more than 90 days as shown in Fig 4 of the paper with only 4 injections. Nagalase activity levels of the mice confirmed the murine survival results.
Yamamoto’s group also compared the potency of two different MAFs (GcMAF and DBPMAF). Only one 100 pg injection of these MAF types given to Ehrlich ascities tumor bearing mice caused them to survive approximately 35 days. When these mice were injected with 100 pg of these MAFs only two or three times, the mice survived for more than 50 days. Post-therapy survival time (e.g., 35 days) should not be referenced while discussing human treatment, since these experiments were done using animal models.
4). Regarding the comments discussing Schndler’s Disease: You have stated that Schindler’s alpha-N-acetylgalactosaminidase is the same as cancerous alpha-N-acetylgalactosaminidase. That is incorrect. Schindlers’s enzyme is a lysosomal enzyme and not secreted to the blood stream. This enzyme is sometimes defined as a constitutive enzyme, because low levels of this enzyme is found in all humans. Its km value = 4.83 X 10-3M while the cancerous enzyme (Nagalase) km value = 1.28 X 10-3 M. Thus, these enzyme km values clearly indicate that they are two different gene products. The cancerous enzyme is an oncogene product. Both of these genes are already gene cloned. Diagnosis of Schindler’s disease can be made by looking for the defect in the Schindler’s enzyme.
5). Regarding the comments discussing GcMAF mimetics produced by ASU. About 15 years ago, Yamamoto’s group established that a trisaccharide on the 420 threonine residue of domain III of Gc1F protein has precursor activity for macrophage activating factor (MAF). They cloned various lengths (80aa peptide) which is safe (patented) and has been very effective in cancer therapy in preclinical models. The preclinical results seen with this cloned MAF (CdMAF) were also shown in the above mouse experiments (Cancer Res 57, 2187-2192, 1997).
anonymous December 18, 2008
See http://www.imminst.org/forum/Gc-macrophase-activating-factor-Gc-MAF-cancer-magic-bullet-t22146.html and especially the PDF at http://www.isbtc.org/meetings/am04/presentations/yamamoto.pdf , which includes a diagram of the forms of Gc protein/GcMAF. If I understand it correctly, Nagalase (alpha-N-acetylgalactosaminase) actually cleaves off the three-sugar group which includes N-acetylgalactosamine (GalNAC). If this is accurate, GcMAF, which only has GalNAC, not the other two sugars, would not be recognized by the Nagalase enzyme.
I don’t know this for sure, but it is what the figure implies and I believe I read it somewhere. I would welcome correction with a solid reference stating otherwise.
JA December 14, 2008
Can someone please clarify why the “Nagalase” enzyme would not theoretically be able to cleave off the GALNac sugar off Gc-maf and deactivate it?? How woudl endogenous Gc-maf bypass enzymatic deactivation by nagalase?? Apparently it is highly likely and is even stated by the researchers at ASU who are developing Gc-maf mimetics.
Wim den Bakker December 14, 2008
Reply to JA, December 7
The “Nagalase” enzyme you mention is normally only active in a tiny organelle lysosomes inside the cell. Lysosomes are organelles that contain digestive enzymes . They digest excess or worn-out organelles, food particles, and engulfed viruses or bacteria.
There are a number of illnesses that are caused by the malfunction of the lysosomes or one of their digestive proteins, e.g., Tay-Sachs disease, or Pompe’s disease (and Schindler disease) . These are caused by a defective or missing digestive protein, which leads to the accumulation of substrates within the cell, impairing metabolism.
So you are right to say that “nagalase” is important for the body, but very probably only inside cells, not in the blood stream.
In fact I find it intriguing why (and how) cancer cells produce “nagalase” and release it in the blood stream. The probable answer of the medical community will be: a genetic mutation, but that doesn’t explain nothing.
Mike M December 11, 2008
you may well believe it’s a breakthrough and should be used as an adjuvant for all cytotoxic therapy but at present there just isn’t anything like enough evidence at present to support that, in terms of either efficacy or safety.
If Gc-MAF is as effective as you suggest then it will indeed be a hugely important breakthrough and will probably earn Yamamoto a Nobel prize, but where’s the evidence? Let’s see some hard data from randomised, double-blind, placebo-controlled trials in a sizeable number of patients, where clinical endpoints are used as a measure of efficacy, not a non-standard surrogate endpoint. Without such evidence, it’s little more than an interesting hypothesis. There are many cancer treatments that promise much in preclinical and early stage clinical trials but ultimately fail to make the grade.
JA December 10, 2008
Yamamoto has definetly caught the tiger by the tail when it comes to the missing link between the immune system activation/deactivation cascade in regards to cancer and HIV; There is no doubt about that, however, this therapy by itself cannot achieve full tumor regression in advanced diseases. Phagocytic activity, or any kind of immune attack cannot out-pace aggressive tumor cell replication. That does not mean that this therapy is not a breakthrough; on the contrary it is HUGE.. Based on all the research, findings and this fundamental role of Gc-MAF in the immune activation cascade, is enough not to warrant all the above mentioned trials. I believe this can be used as an adjuvant to any form of cytotoxic therapy (conventional or alternative) as well as used post operatively after primary tumor ressection to prevent distal metastatic spread, and any short term and possibly long term relapses. In essence this can be a “curative” post surgical therapy and can replace “prophylactic” chemotherapy easily based on chemo’s failed track record for being targeted. This universal approach is based on inherent fundmental biology and warrants more attention.
Kat Arney December 10, 2008
We’d like to address some of Lilly’s comments .
We’re not dismissing Yamamoto’s research in its entirety. We’re more concerned with the fact that his results are being touted around on the internet as a “cure for cancer”, when in fact the actual scientific evidence to support this claim is shaky. We’d like to see much more research done in this area before we’re happy that this is really an effective treatment, as we’re not convinced by the current results.
To address Lilly’s specific points:
We’re not arguing that this is a failed experiment, but pointing out that the mice treated in the experiments still died with an overwhelming tumour burden. It is a long leap from there to the trials claiming to have “cured” patients.
The issue here is the design of meaningful clinical trials. There are a number of different types of trials, designed to show different things.
Phase 1 and 2 clinical trials are carried out on small groups of patients (often less than 20). These are patients who are terminally ill with cancer, who have tried all the treatment options available to them and usually have a relatively short time left to live.
Typically, phase 1 and 2 trials would involve testing a new drug for the very first time in patients, starting with a small dose to check for any potential side effects, and eventually escalating up to the maximum tolerated dose (MTD).
The main aim of these kind of trials is not to cure or treat the patients, as usually their cancer is far too advanced. Researchers will ask questions about how the drug is used by the body, if it is affecting the molecular pathways it was designed to target, and if it is affecting the tumours in any way.
There are also larger scale, phase 3, clinical trials. These involve a larger number of patients, and would have a group receiving the new treatment, and a control group receiving the current gold standard treatment for the disease (or a placebo if no effective current treatment exists).
Looking at the Yamamoto papers, it’s not entirely clear what sort of trial they are running. They don’t fit the criteria for a phase 1 or 2 trial, as there’s no evidence that these patients were terminally ill with advanced disease, and it’s not the usual dose-escalation study.
And if the trial was a standard phase 3 design, then there should certainly be a control group of patients who were not receiving Gc-MAF, and the sample size would need to be much larger, to avoid statistical bias.
This is the fundamental issue. Without a control group, and effective monitoring of the patients, it is impossible to prove that it was the effects of the Gc-MAF treatment controlling their cancer, and not the effects of the other treatment they had received. As explained above, the trial design in Yamamoto’s papers doesn’t provide meaningful data about the effectiveness of Gc-MAF.
As mentioned in the original post, Yamamoto provides no evidence of the TNM status of any of the patients (which would indicate the severity of their disease). Without this kind of data, it’s impossible to say whether the treatment has actually had an effect, or whether the patients would have survived anyway.
Eight out of ten patients on average survive breast cancer for at least five years. Survival rates are higher for those whose cancers have spread little, and lower for those whose cancers are advanced. Without the data to show how advanced the patients’ cancers actually were, the results are essentially meaningless.
Yamamoto maintains that nagalase activity is a direct measure of metastasis, but this is by no means a standard measure, and has only been verified by his own experiments. Including TNM status – an internationally verified measure of tumour spread – at the start of the experiment should be a fundamental part of a trial like this.
Without this data, the results are difficult to interpret, as he is measuring against his own yardstick, rather than accepted standards. Any researcher looking to demonstrate the effectiveness of a new treatment should provide this kind of data by default. The fact that it is missing weakens his argument..
The healthy patient was not part of the trial as far as we can tell. In the papers, a typical measurements of nagalase in a healthy person is mentioned. But in the context of a clinical trial this is meaningless. Without the measurements of nagalase levels (and survival) in a control group, the trial doesn’t really provide much information, except to tell us that Gc-MAF is safe to give to cancer patients at the doses used.
This is true, but the chemotherapy and radiotherapy that the patients received could be responsible for their survival – without a control group, there is simply to way to tell at all.
We are certainly not saying that we’ll only look at publications if they are in the highest impact journals. Given the huge amount of cancer research that is published every year, this would be an impossible demand. But truly important breakthroughs in science – as the Sardi article would have us believe this is – are generally reported in high impact journals (for example this story was published in the NEJM).
The articles on the web about Yamamoto’s work are claiming that it is a 100 per cent cure for cancer. If the peer reviewers at the big end journals also believed this, based on the results presented in the papers, then surely they would leap at the chance to publish them? The fact that such “groundbreaking” results have not been published in higher impact journals suggests that the experts don’t think they’re all they are purported to be.
You have misinterpreted our views on this. We’re not intending to dismiss research into the immune system, and how we can use it to tackle cancer through immunotherapy. As mentioned, there are thousands of researchers around the world, including those funded by Cancer Research UK, who are doing just that. There’s no doubt as well that Gc-MAF is certainly an interesting avenue of research but, as I’ve explained, we’re just sceptical that this is a “cure for cancer”, at least at this stage.
We agree that Yamamoto himself is not claiming that Gc-MAF is a “magic bullet”. As we’ve said, we are more concerned that his results are being reported as a 100 per cent cure for cancer, when the scientific evidence to support this is shaky.
As an organisation, we embrace new research into treating cancer, but we do not want to give patients false hope. Yamamoto’s results are interesting, but a lot more rigorous scientific research needs to be done to prove that Gc-MAF is an effective treatment for any type of cancer.
Lilly December 8, 2008
There are some obvious holes in the criticism provided by Kat. Let’s start under the section marked “macrophage”. She claimed that Yamamoto’s work published in 1997 only improved survival of the mice tested from 16 to 35 days and that the mice eventually died anyway. This is true, although it needs to be stated that the control group, who did not receive any administration of the MAF lived about 16 days post inocculation, whereas the group who received one administration of MAF and the same inocculation of cancerous cells lived on average 35 days. This was with one administration only…..this is huge actually. And should be noted as such…not stated as a failed attempt. Yamamoto was only trying to evaluate the response to very small numbers of administrations, where now he has evolved to understand the need for weekly injections of MAF, until healthy, control-levels of NAGALASE are reached.
“clinical trials” section: This section suggests that this is not an amazing breakthrough because there were too few patients whose cancers were “cured”. Yes, typically what is necessary and considered to be good science is to have large scale studies with placebo controls and randomization ect, however we are blogging about a breakthrough, which does not require these types of numbers, it only needs enough numbers to show that it is worth going to the next level. And when looking at these studies the cancer free periods post therapy were between 4 and 15 years, which included 100% of the patients. I would not only say this is a true breakthrough, but it is mind bending!! Hey, it only takes 5 years being cancer free before you are eligible for that disability policy, because we refer cautiously in the medical world to the 5 year mark as being significant in a cancer patient reaching a cure for themselves. Yamamoto’s work supports all of that. The author was concerned that the trial designed was flawed by the fact that patients had all ready had current standard of care therapies prior to their taking part in these trials. This is a non-issue. The tie that binds this trial together was the fact that all of the patients exhibited increased NAGALASE levels, which have been all ready accepted as being associated with tumor burden. In fact, there was even the healthy, non-cancer patient whose blood values were used as control. A good design. The author also said that researchers did not monitor the patients. They did. The NAGALASE levels were drawn and compared against the control as well as decreasing tumor markers….ie..CEA,CA15-3, CA27,29 as well as CT scans of the patients. So, this is just inaccurate. The patients were monitored continuously with even a variety of modalities that all well accepted in the field of oncology. You can’t have more monitoring. The author was discouraged that the patient’s TNM status was not given, however Yamamoto did address this issue right up front in the first paragraph, in which he states that there is even concern over a third of women who are considered to be node-negative that they will have recurrence. So, in essence, I believe he is feeling that there is some concern with utilizing this TNM status as a prognostic indicator because it is not sensitive enough to correctly evaluate a women’s chances of recurrence and therefore we should be mindful of it value as a predictive tool…again …score Yamamoto!
MAF precursor activity was followed in order to support that the macrophages were actually becoming activated. And once again there were contols used, meaning a standard NAGALASE measurement typical of a healthy person with out cancer. 80% of metastatic cancer patients do not live for at least 5 years….and that is the patient population being studied.
Dr Yamamoto has a long history of publications, which anyone can pubmed and see. we need forward thinkers, inorder to move forward and those who are willing to work slightly outside the confines of our extremely political medical community…although, I suppose many of you med students think if it wasn’t in the New England Journal of Medicine…it never happened. Please open your eyes a bit wider…things are going to get missed.
There is a huge amout of research being conducted in this area right now…other scientists are really getting on the bandwagon and recognizing the potential that the immune system can offer in terms of cancer. OOPs….it is hard not to point out the author’s statement that other scientists would “jump on the bandwagon” in researching this area if there was something here..and implicating that others are not..yet read the next paragraph where she mentions the research going on by her group in this area…hmmmmm oopsie…scratching my head now??? ok..so that must mean…ya…lots of scientists are jumping on this bandwagon, including many cancer research UK-funded scientists…so this lends itself to support the work being done by yamamoto?….I think that is it…ya..got it.
to sum up
I don’t see anything in the research about Dr. Yamamoto suggesting that this is a “magic bullet” he is simply conducting and publishing his research and to say that he has not shown some breakthroughs would really be insulting and just plain foolish.