A macrophageNote: This post has been updated as several research papers about Gc-MAF have been retracted.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]

Clinical trials

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]

Further problems

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:

*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]